Methods and systems for reducing neural activity in an organ of a subject

ABSTRACT

The present disclosure provides, according to some embodiments, methods and systems for selectively reducing, blocking or inhibiting at least part of the neural activity in an organ of a subject. In preferred embodiments, the method and system are used for selectively blocking at least part of the neural activity in a duodenum of a subject in need thereof. According to some embodiments, the selective blocking occurs through use of laser radiation. According to some embodiments, the selective blocking comprises causing damage to at least part of sensory nerves located within a target area while maintaining functional activity of tissue surrounding the sensory nerves. According to some embodiments, the sensory nerves include neurons configured to transmit signals triggered by food passing through the duodenum, such as, but not limited to, neurohormonal signals.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit from a U.S. patent application Ser. No.14/763,514 filed on Jul. 26, 2015, which claims the benefit from aNational Phase of PCT Patent Application No PCT/IL2014/050109 filed onJan. 30, 3014, which claims benefit from U.S. Provisional Patent Nos.61/758,816 and 61/835,597, both entitled “ENDOLUMINAL INTERVENTIONS FORMANAGEMENT OF TYPE 2 DIABETES, INSULIN RESISTANCE AND OBESITY”, filed onJan. 31, 2013 and Jun. 16, 2013, respectively. The full disclosures ofall of the above-cited references are hereby incorporated by referenceherein.

TECHNICAL FIELD

The present disclosure relates generally to methods and systems forselectively blocking part of the neural activity in a bodily organ. Inpreferred embodiments, the methods and systems are used for selectivelyblocking part of the neural activity in the small intestine, andpreferably in the duodenum of a subject. In preferred embodiments, theinvention is directed at endoluminal interventions that block, modulateand/or impact neurohormonal and other signals triggered by food passingthrough the gastrointestinal (GI) tract.

BACKGROUND

As opposed to Type 1 Diabetes mellitus, in which there is an absoluteinsulin deficiency due to destruction of islet cells in the pancreas,Type 2 Diabetes mellitus (T2D), formerly known as noninsulin-dependentdiabetes mellitus (NIDDM) or adult-onset diabetes, 1s a metabolicdisorder characterized by high blood glucose and a relative insulindeficiency due to insulin resistance. Type 2 diabetes constitutes about90% of cases of diabetes worldwide and demonstrates an increasinglygrowing rate of prevalence. Type-2 diabetes is typically managed bychanges in lifestyle, such as exercise and dietary modification, and incertain cases by medications and surgery.

Obesity is thought to be one of the primary causes of type 2 diabetes,especially in people who are genetically predisposed for the disease.Obesity is often treated by performing a bariatric surgery procedure(also known as weight-loss surgery) on the gastrointestinal tract of anobese patient in order to reduce weight. Multiple clinical studies andreports have indicated that in addition to weight-loss, certainbariatric surgery procedures can contribute to remission or improvementin disease management of type-2 diabetes, as well as to reduction ininsulin resistance. This is specifically the case in certain bariatricprocedures that bypass the proximal part of the gastrointestinal (GI)tract, such as Roux-en-Y gastric bypass (RYGB), duodenal-jejunal bypass(DJB) surgery and gastrojejunal bypass (GJB) surgery, all aimed atbypassing the duodenum. Unfortunately, bariatric surgery is associatedwith high risk and high cost and is not the optimal solution formanagement of the majority of T2D and non-obese patients, estimated athundreds of millions worldwide. Thus, bariatric surgery is not used inthe majority of T2D patients for disease management.

Previous attempts to obtain effects similar to bariatric surgery haveincluded the use of minimally invasive devices, such as those insertedendoluminally. Such attempts have included use of staplers to reducestomach size, insertion of devices into the stomach (most common ofwhich is the intra-gastric balloon), implantation of electricalstimulators that intervene with stomach function (gastric electricalstimulation) via the modulation of gastric nerves activity, use ofsleeves that bypass the duodenum such as the EndoBarrier® (GI Dynamics™)and radio-frequency (RF) ablation applied to the surface of the organ inthe gastrointestinal tract with non-penetrating electrodes, as describedin US Patent Publication No. 2008/0275445 A1 assigned to BarrX, or in WO2012099974 A2 assigned to Fractyl Laboratories, Inc., which targetsduodenum mucosa, and ablation of the area around the pyloric sphincteras described in EP1567082 A1 to Curon.

Each of these methods, however, suffers from inherent limitations. Forexample, use of the EndoBarrier® is associated with adverse events andhas unwarranted side effects, such as vomiting, nausea, abdominal pain,mucosal tear, bleeding, migration and obstruction, necessitating earlydevice removal. (Verdam F J et al. Obesity 2012, Vol 2012) The use ofstaplers suffers from complications and failed to show the effectivenessof surgery. The use of intra-gastric balloons suffers from side effects,such as migration. The use of gastric electrical stimulation suffersfrom limited efficacy.

Accordingly, it is desired to provide a novel solution for endoluminalinterventions that will overcome the deficiencies of the prior art.

The foregoing examples of the related art and limitations relatedtherewith are intended to be illustrative and not exclusive. Otherlimitations of the related art will become apparent to those of skill inthe art upon a reading of the specification and a study of the figures.

SUMMARY

The following embodiments and aspects thereof are described andillustrated in conjunction with systems, tools and methods that aremeant to be exemplary and illustrative, not limiting in scope.

The present disclosure provides, according to some embodiments, methodsand systems for selectively blocking, reducing or limiting part of theneural activity in a target area by directing laser radiation configuredto cause damage to sensory neurons located within the target area.According to some embodiments, the target area is located in an organ ina subject's body. According to some embodiments, the target area islocated in the small intestine or a wall of the duodenum.

According to some embodiments, the method and systems are forselectively blocking, reducing or limiting part of the neural activitywithin a duodenal wall or in contact with a duodenal wall in a subject.According to some embodiments, the methods and systems cause damage tosensory neurons in the target area, while maintaining functionalactivity of tissue surrounding the sensory neurons. According to someembodiments, the tissue surrounding the sensory neurons is not affectedby the methods and systems, such that the methods and systems arelocalized only to sensory neurons in the target area.

According to some embodiments, the sensory neurons are sensory neuronsactivated by passage of food through the duodenum. According to someembodiments, the sensory neurons are activated by signals received bymechano-sensors and/or chemo-receptors in at least one layer of theduodenal wall. Each possibility represents a separate embodiment of thepresent disclosure. According to some embodiments, the sensory neuronsare neurons which deliver internal neural signals within the duodenum.According to other embodiments, the sensory neurons are neurons whichdeliver signals out of the duodenum through neurons such as, but notlimited to, vagal nerves, sympathetic nerves and parasympathetic nerves.

According to some embodiments, the methods and systems block and/ormodulate neurohormonal and other signals triggered by food passingthrough the GI tract while minimizing side effects by selectivespatially localized interventions.

According to some embodiments, the methods and systems include laserradiation configured to specifically target at least one target area,the target area comprising sensory neurons. According to someembodiments, the target area may include one or both extrinsic andintrinsic neural pathways. According to some embodiments, the laserradiation is focused on a target area comprising sensory neurons suchthat tissue surrounding the target area maintains functional activity.According to a non-limiting example, pulsed laser radiation may be usedand ablation may occur only within the target area on which the laserradiation is focused. According to some embodiments, the laser radiationis focused on a target area such that only neurons within the targetarea are damaged, while non-neural tissues within the target areamaintain functional activity. According to some embodiments, the laserradiation is focused at an intensity and/or duration such that itinduces thermal damage in neural tissue within the target area andinduces no damage or minimal damage to tissue other than neural tissuewithin the target area. Each possibility represents a separateembodiment of the present disclosure. Without wishing to be bound by anytheory or mechanism, neural tissue is more sensitive to thermal damagethan tissues such as, but not limited to, blood vessels, muscle tissueand lymphatic vessels, thus enabling to direct thermal damagespecifically to neurons within a target area.

Advantageously, using laser radiation to selectively induce damage tosensory neurons within the duodenal wall without damaging functionalactivity of other duodenal tissues may enable efficient treatment ofmedical conditions such as, but not limited to, obesity and type-2diabetes, while inducing minimal side effects. Without wishing to bebound by any theory or mechanism, the methods of the disclosure preventsensing of food-passage through the duodenum. Thus, according to someembodiments, the disclosed methods lead to modulation of the metabolicbalance and/or motility and/or physiology of the gastrointestinal tractin a way which enables treatment/amelioration of medical condition suchas obesity and/or type-2 diabetes. According to some embodiments, themethods of the invention are able to treat/ameliorate a medicalcondition such as, but not limited to, obesity and/or type-2 diabeteswithout impeding duodenal functions not related to treatment of theconditions, such as, but not limited to bicarbonate secretion,maintenance of fluid/electrolyte imbalance and function of duodenalvilli.

According to some embodiments, the laser radiation is deliveredendoluminally from the duodenal lumen towards at least one target areacomprising sensory nerves, the target area residing being within theduodenal wall or in contact with the duodenal wall. Each possibilityrepresents a separate embodiment of the present disclosure. According tosome embodiments, the present disclosure provides minimally invasivesolutions for endoluminal interventions that selectively block, reduce,limit and/or modulate neuronal activity triggered by food passingthrough the gastrointestinal (GI) tract, typically through the duodenum,while minimizing side effects by selective spatially localizedinterventions. According to a non-limiting example, signals triggered byfood passing through the GI are neurohormonal signals. According to someembodiments, the target area for intervention may include intrinsicneural pathways, extrinsic neural pathways or a combination thereof.Each possibility represents a separate embodiment of the presentdisclosure. In certain embodiments, blocking, reducing, limiting ormodulating neural activity comprises at least one of: impacting,denervating, modifying, ablating, damaging, severing or otherwiseimpeding at least part of the neurons in the target area. According tosome embodiments, the neurons targeted by the methods of the disclosureare sensory neurons. According to certain embodiments, the neuronstargeted by the methods of the disclosure are motor neurons, such as,but not limited to, motor neurons affecting motility of the smallintestine.

According to some embodiments, methods, systems and apparatuses areprovided to block and/or affect neural signals generated when a mealpasses through the duodenum by impacting, denervating, modifying,blocking, ablating, damaging, cutting, severing or otherwise impedingneural activity of the plexus that reside in the submucosa of theduodenal wall (the submucosal or Meissner's plexus) that transmitslocally as well as to extrinsic nerves, such as the Vagal and Ganglia,parasympathetic & sympathetic nerves, signals acquired through thepassage of food through chemical sensors in the duodenum.

According to some embodiments, methods, systems and apparatuses areprovided for modifying, impacting, blocking, ablating, cutting,damaging, severing or otherwise impeding neural activity of the plexusthat reside in the tunica muscularis of the duodenal wall (theAuerbach's plexus or Myenteric plexus), the method and apparatus canenable blocking of signals from mechano-sensors and otherchemo-receptors that pass through the Myenteric plexus.

According to some embodiments, methods, systems and apparatuses areprovided for modifying, impacting, blocking, ablating, cutting,damaging, severing or otherwise impeding neural activity of theinterconnecting synapses and/or other elements of the enteric nervoussystem (ENS) preferably the intrinsic nervous system that reside withinthe duodenum wall.

According to some embodiments, methods, systems and apparatuses areprovided to block and/or affect signals generated when a meal passesthrough the duodenum by impacting, denervating, modifying, blocking,ablating, damaging, severing or otherwise impeding neural activity ofthe local Vagal and Ganglia, parasympathetic & sympathetic nerves at theinterface with the duodenum (and/or jejunum) wall or close to it.

According to some embodiments, methods and apparatus are provided to“blind” the duodenum to the meal, chime and nutrients traversing intothe intestines from the stomach. This modulates and impacts themetabolic balance and/or motility and/or impacts GI physiology in linewith the “foregut hypothesis” set forth by several publications (such asCummings D E et al. 2004; Pories W. J. et al. 2001; Rubino F. et al.2002, 2004, 2006; incorporated herein as reference in their entirety).In particular, it has been proposed that this region of the intestinesmay play a significant role in the development of T2D whenoverstimulated with nutrients insusceptible individuals, for example viathe induction of a putative signal that promotes insulin resistance andT2D.

According to some embodiments, the impact of plexus is obtained byseveral impacts across the GI lumen in a form of at least part of acircle to leave most of the tissue without any impact and reduce sideeffects of intervention.

According to some embodiments, the impact of plexus is obtained byseveral impacts across the GI lumen in targeting inner layers of theduodenum wall and in a form of at least part of a circle to leave mostof the tissue without any or minimized impact and reduce side effects ofintervention.

According to some embodiments, the impact of plexus is obtained byseveral impacts across the GI lumen in targeting inner layers of theduodenum wall and in a form of line along the lumen to leave most of thetissue without any impact and reduce side effects of intervention.

According to some embodiments, elements of the enteric nervous system(ENS), the intrinsic nervous system, are targeted to modulate itsfunction upon passage of a meal through the duodenum and/or stomach.Chemical substances such as antibodies may be used according to someembodiments of the present invention to selectively target elements ofENS. According to some embodiments such chemical substances provideselectivity of targeting elements of the nervous system present withinthe tissue wall.

According to some embodiments, the blocking of the signals triggered byfood either by chemical sensors or mechanical sensors may also modulatemotility related functions of the GI tract organs, such as modulation ofgastric accommodation and relaxation triggered by a meal passing throughthe duodenum and/or stomach.

According to some embodiments, this object is achieved by providing amethod to block and/or affect signals generated when a meal passes alsothrough the jejunum.

According to some embodiments, this object is achieved by providing aninstrument to block and/or affect signals generated when a meal passesalso through the jejunum.

According to one aspect, the present disclosure provides a method forreducing neural activity in an organ of a subject, the methodcomprising:

introducing at least one laser emitting device into the organ;

emitting a focused laser beam from the laser emitting device to contacta target area on or beneath a wall of the organ and thereby damage atleast one sensory nerve located at the target area to at least partiallyreduce the neural activity.

According to some embodiments, the present disclosure provides a methodfor blocking at least part of the neural activity in an organ of asubject in need thereof, the method comprising:

-   -   introducing at least one laser element into the organ; actuating        the laser element to emit laser radiation;    -   focusing the laser radiation to a target area within or in        contact with at least part of the wall of the organ, wherein the        target area comprises sensory nerves, such that the radiation is        configured to cause or induce damage to at least part of the        sensory nerves. Each possibility represents a separate        embodiment of the present disclosure.

According to some embodiments, functional activity of tissue surroundingthe sensory nerves is maintained, despite damage being caused to the atleast part of the sensory nerves. According to some embodiments, damageto at least part of said sensory nerves occurs while maintainingfunctional activity of tissue surrounding said sensory nerves.

According to some embodiments, the organ is a small intestine orduodenum. According to some embodiments, the wall of the organ is thewall of the duodenum or the duodenal wall. According to someembodiments, the organ is a duodenum and includes a duodenal wall.According to some embodiments, the organ comprises a duodenum and thewall comprises a duodenal wall.

According to some embodiments, causing damage to said sensory nervescomprises thermal damage. According to some embodiments, the laserradiation is configured to heat said target area to 45-75° C. Accordingto some embodiments, causing damage to sensory nerves comprises ablationof said target area. According to some embodiments, said laser radiationis pulsed laser radiation. According to some embodiments, causing damageto said sensory nerves comprises causing mechanical damage. According tosome embodiments, the laser beam is configured to heat the target areato 45-75° C. According to some embodiments, emitting the focused laserbeam comprises ablating the at least one sensory nerve. According tosome embodiments, the focused laser beam causes thermal damage to the atleast one sensory nerve comprises causing mechanical damage. Accordingto some embodiments, the focused laser beam is configured to heat theone or more target areas to a temperature of 45-75° C.

According to some embodiments, the target area comprises at least partof Meissner's plexus, Auerbach's plexus or both. Each possibilityrepresents a separate embodiment of the present disclosure. According tosome embodiments, the target area comprises at least part of theMeissner's plexus. According to some embodiments, the target area iscomprised in a sub-mucosal layer of the duodenal wall. According to someembodiments, the target area is comprised in a tunica muscularis layerof the duodenal wall. According to some embodiments, the target area iscomprised in a mesenteric layer interfacing with the duodenal wall.According to some embodiments, the target area comprises at least partof an area selected from the group consisting of a Meissner's plexus andan Auerbach's plexus. Each possibility represents a separate embodimentof the present disclosure. According to some embodiments, the targetarea is selected from the group consisting of: a sub-mucosal layer ofthe duodenal wall, a tunica muscularis layer of the duodenal wall and amesenteric layer interfacing with the duodenal wall.

According to some embodiments, the subject is afflicted with a medicalcondition selected from the group consisting of: obesity, type 2diabetes, insulin resistance and a combination thereof. Each possibilityrepresents a separate embodiment of the present disclosure.

According to some embodiments, the sensory nerves are configured to beactivated by food passing through the duodenum. According to someembodiments, the sensory nerves are configured to transmit signals frommechano-sensors and/or chemo-receptors located within said duodenalwall. Each possibility represents a separate embodiment of the presentdisclosure. According to some embodiments, the mechano-sensors and/orchemo-receptors are configured to be activated by food passing throughthe duodenum. According to some embodiments, causing damage to saidsensory nerves results in blocking signals from mechano-sensors and/orother chemo-receptors located within said duodenal wall. Eachpossibility represents a separate embodiment of the present disclosure.

According to some embodiments, the at least one sensory nerve comprisesat least one nerve that transmits signals from at least one ofmechano-sensors or chemo-receptors located within the duodenal wall.According to some embodiments, the mechano-sensors or chemo-receptorsare activated by food passing through the duodenum. According to someembodiments, damage to said at least one sensory nerve results inblocking signals from at least one of mechano-sensors or chemo-receptorslocated within the duodenal wall.

According to another aspect, the present disclosure provides a catheterfor reducing neural activity in an organ of a subject, the cathetercomprising:

-   -   an elongate catheter body having a proximal end and a distal        end;    -   a laser emitting element coupled with the catheter body at or        near the distal end and configured to emit a focused laser beam;        and    -   a rotatable optical element coupled with the laser emitting        element and configured to direct the focused laser beam to one        or more target areas on or beneath a wall of the organ, wherein        the target area comprises at least one sensory nerve, such that        the laser beam is configured to cause damage to the at least one        sensory nerve.

According to some embodiments, the present disclosure provides acatheter for blocking at least part of the neural activity in an organof a subject in need thereof, the catheter comprising:

a laser element configured to emit laser radiation; and

a rotatable optical element configured to direct the laser radiation toone or more target areas within or in contact with at least part of awall of the organ, wherein the target area comprises sensory nerves,such that the radiation is configured to cause damage to sensory nerves.

According to some embodiments, functional activity of tissue surroundingthe sensory nerves is maintained, despite damage being caused to the atleast part of the sensory nerves. According to some embodiments, thecatheter comprises an endoluminal duodenal catheter. According to someembodiments, the catheter is an endoluminal duodenal catheter. Accordingto some embodiments, the laser element comprises at least one opticalfiber. According to some embodiments, the laser emitting elementcomprises at least one optical fiber. According to some embodiments, thelaser radiation is pulsed laser radiation. According to someembodiments, emitting the focused laser beam comprises emitting pulsedlaser radiation. According to some embodiments, the laser beam comprisespulsed laser radiation. According to some embodiments, the focused laserbeam comprises pulsed laser radiation. According to some embodiments,the rotatable optical element deflects the laser radiation at an angleof 90 degrees from a longitudinal axis of the catheter. According tosome embodiments, the rotatable optical element deflects the laser beamat an angle of 90 degrees from a longitudinal axis of the catheter body.According to some embodiments, the rotatable optical element deflectssaid laser radiation through an aperture in the catheter. According tosome embodiments, the rotatable optical element is located within thedistal head of the catheter. According to some embodiments, therotatable optical element is located within the laser element locates atthe distal head of the catheter. According to some embodiments, theorgan is a small intestine or duodenum. According to some embodiments,the wall of the organ is the wall of the duodenum or the duodenal wall.According to some embodiments, the catheter is an endoluminal duodenalcatheter.

According to some embodiments, the laser element comprises a rotatableoptical element configured to focus said laser radiation to a pluralityof target areas along a circular trajectory within said duodenal wall orin contact with said duodenal wall. Each possibility represents aseparate embodiment of the present disclosure. According to someembodiments, the rotatable optical element comprises a rotatable prism.According to some embodiments, the rotatable optical element is arotatable prism. According to some embodiments, the rotatable opticalelement comprises a beam-splitter prism that defects the laser beam intoa first beam of laser radiation that is focused on the target area and asecond beam of laser radiation that is focused on a detector. Accordingto some embodiments, the rotatable optical element is a beam-splitterprism that defects the laser radiation into a first beam of laserradiation that is focused on said target area and a second beam of laserradiation that is focused on a detector. According to some embodiments,the catheter further comprises at least one lens element. According tosome embodiments, the laser element within the catheter furthercomprises at least one lens element. According to some embodiments, thecatheter further composes a lens coupled inside the catheter body.According to some embodiments, the catheter further comprises at leastone lens coupled inside the catheter body. According to someembodiments, the lens element is a correction lens element forcorrecting aberration. According to some embodiments, the lens comprisesa correction lens for correcting aberration.

According to some embodiments, the laser emitting device composes arotatable optical element configured to focus the laser beam to aplurality of target areas along a circular trajectory on or within theduodenal wall.

According to some embodiments, the rotatable optical element is selectedfrom a group consisting of a wide-angle lens, a dove prism, a reversionor “K” prism, a Delta or Pechan prism, a dispersive prism, a reflectiveprism, a beam-splitting prism, a deflective prism, a triangular prism, atrapezoidal prism, a Olan-Taylor prism or a Glan-laser prism, ahigh-powered laser-light right angle prism, a retroreflector andcombinations thereof. Each possibility represents a separate embodimentof the present disclosure. According to some embodiments, the opticalelement is a wide-angle lens system. According to some embodiments, theoptical element is a lens capable of correcting f-theta distortion orf-sin(theta) distortion. According to some embodiments, the systemfurther includes a focusing element that is positioned before therotatable optical element and is not rotated, with long enough focallength to enable focusing on a target after. According to someembodiments, the rotatable optical element is a dove prism, a reversionor “K” prism, a Delta or Pechan prism, or any other associated prismknown in the art. According to other embodiments, the rotatable opticalelement is a dispersive prism, a reflective prism, a beam-splittingprism or a deflective prism. According to some embodiments, the prism isa low-loss deflective prism. According to some embodiments thedispersive prism is a triangular, a Pellin-Broca prism, an Abbe Prism ora compound prism.

According to other embodiments, the prism has a triangular ortrapezoidal shape. According to other embodiments, the form of the prismis made from glass (i.e., BK7 glass) and is designed for an adequatelaser beam.

According to other embodiments, the prism is a Gian-Taylor prism or aGian-laser pnsm. According to other embodiments, the prism is anequilateral glass prism.

According to other embodiments, the prism is selected from a groupconsisting of anamorphic Prism Pairs, a high-powered laser-light rightangle prism, a hollow retroreflector, a laser-line right angle prism, aN-BK7 Corner Cube Retroreflector or a UV Fused Silica Corner CubeRetroreflector.

According to some embodiments, a prism compressor or a pulse compressoris used in conjunction with the prism.

According to some embodiments, a mirror is used instead of a beam tomanipulate the beam. According to some embodiments imaging tools areused to select the target and align focal plane in the target. Accordingto some embodiments the lumen and/or the duodenal wall is manipulated todetermine/force the target area to be within a preset focal plane. Eachpossibility represents a separate embodiment of the present disclosure.According to some embodiments laser is selected to absorb energy andelevate temperature at the target, according to some embodiments pulsedlaser is selected to modify tissue by mode of ablation or similar.According to some embodiments the interface with vagal or ganglionextrinsic nerves is targeted. According to some embodiments a laser beamis linearly scanned in the interface according to some embodiments meanto create a linear, line, spot at the target is used.

According to some embodiments, the optical element can control theorientation of the focused beam around the axis of the duodenum and thesame or other element can scan the spot beam over the duodenum axis.According to some embodiments, the optical element can control theorientation and a line spot is generated without need to scan by meanssuch as diode array, using a diffusing fiber with optics. According tosome embodiment, the laser element comprises a non-rotatable opticalelement. According to some embodiments, the non-rotatable opticalelement is configured to induce a line impact on a target area, such as,but not limited to, a target area at the interface of the duodenum witha vein-artery-nerve (VAN) complex.

According to some embodiments, the catheter further comprises anactuator for rotating the rotatable optical element. According to someembodiments, the catheter further comprises an actuator coupled with therotatable optical element for rotating the rotatable optical element.According to some embodiments, the catheter further comprises acontroller for controlling the actuator in accordance with an inputsignal from an input device. According to some embodiments, the catheterfurther comprises a controller coupled with the actuator for controllingthe actuator in accordance with an input signal from an input device.According to some embodiments, the catheter comprises a handle coupledwith the catheter body at or near the proximal end, wherein the inputdevice is coupled with the handle. According to some embodiments, thecatheter is used with an endoscope. According to some embodiments, thecatheter body has an outer diameter selected to fit through with a lumenof an endoscope.

According to another aspect, the present disclosure provides a systemfor reducing neural activity in at least one neural region in an organof a subject, the system comprising:

a catheter comprising:

-   -   an elongate catheter body having a proximal end and a distal        end;    -   a laser emitting element coupled with the catheter body at or        near the distal end and configured to emit a focused laser beam;        and    -   a rotatable optical element coupled with the laser emitting        element and    -   configured to direct the focused laser beam to one or more        target areas on or beneath a wall of the organ, wherein the        target area comprises at least one sensory nerve, such that the        laser beam is configured to cause damage to the at least one        sensory nerve.

According to some embodiments, the present disclosure provides a systemfor use in blocking at least part of the neural activity in at least oneneural region in an organ of a subject in need thereof, the systemcomprising:

-   -   a catheter for blocking at least part of the neural activity in        the organ of a subject in need thereof, the catheter comprising:        -   a laser element configured to emit laser radiation; and        -   a rotatable optical element configured to direct the laser            radiation to one or more target areas within or in contact            with at least part of a wall of the organ, wherein the            target area comprises sensory nerves, such that the            radiation is configured to cause or induce/trigger damage to            sensory nerves. Each possibility represents a separate            embodiment of the present disclosure.

According to some embodiments, the rotatable optical element is furtherconfigured to focus the laser radiation to said one or more targetareas, wherein the energy at the target area is focused to be above thatof a surrounding area. According to some embodiments, the system furtherincludes an imaging device configured to capture structural informationrelated to the duodenal wall or an area in contact with at least part ofthe duodenal wall. According to some embodiments, the imaging device isan endoscope. According to some embodiments, the imaging device isselected from the group consisting of: an optical imaging device,thermal imaging device, ultrasonic imaging device, Near Infra-Redimaging device, Infra-Red imaging device, Optical Coherence Tomography(OCT) based imaging device and combinations thereof. Each possibilityrepresents a separate embodiment of the present disclosure. According tosome embodiments, the imaging device comprises an endoscope.

According to some embodiments, the structural information comprises alocation of layers of said duodenal wall. According to some embodiments,the structural information comprises a location of a mesenteric layer incontact with the at least part of the duodenal wall. According to someembodiments, the structural information comprises a location of amesenteric layer in contact with the duodenal wall.

According to some embodiments, the system further includes a controllerconfigured to determine the one or more target areas based on thestructural information.

According to some embodiments, the organ is a small intestine orduodenum. According to some embodiments, the wall of the organ is thewall of the duodenum or the duodenal wall. According to someembodiments, the catheter is an endoluminal duodenal catheter.

According to some embodiments, the laser element comprises at least oneoptic fiber. According to some embodiments, the optical element is arotatable optical element. According to some embodiments, the rotatableoptical element is a prism.

According to some embodiments, functional activity of tissue surroundingthe sensory nerves is maintained, despite damage being caused to the atleast part of the sensory nerves. According to some embodiments thedamage is not immediate but laser or other energy modalities triggerprocesses that lead to injury and death. According to some embodiments,emitting the focused laser beam comprises damaging the at least onesensory nerve without adversely affecting functional activity of tissuesurrounding the at least one sensory nerve.

According to some embodiments, the system further comprises at least onepressure-inducing element configured to exert pressure on at least partof said duodenal wall. According to some embodiments, the system furthercomprises at least one pressure-inducing element coupled with thecatheter body and configured to exert pressure on at least part of thewall of the organ. According to some embodiments, the at least onepressure-inducing element is in the form of a balloon. According to someembodiments, the at least one pressure-inducing element comprises aballoon. According to some embodiments, the at least onepressure-inducing element is configured to hold said laser element inplace. According to some embodiments, the at least one pressure-inducingelement is configured to hold the laser emitting element in place.According to some embodiments, the at least one pressure-inducingelement is configured to manipulate the duodenal wall such that apre-set optical path is achieved between the laser element and targetarea. According to some embodiments, the system further comprises acontroller configured to determine the pressure exerted by the at leastone pressure-inducing element. According to some embodiments, thecontroller is configured to adjust the pressure exerted by said at leastone pressure-inducing element, typically so that a pre-set optical pathis achieved between said laser element and target area.

According to another aspect, the present disclosure provides a methodfor reducing neural activity in an organ of a subject, the methodcomprising:

-   -   advancing a distal end of a flexible, laser emitting catheter        into a small intestine of the subject;    -   identifying a target area on or beneath a wall of the small        intestine; and    -   emitting a focused laser beam from the laser emitting catheter        to contact the target area and thereby damage at least one        sensory nerve located at the target area to at least partially        reduce the neural activity.

According to some embodiments, identifying the target area is performedusing a visualization device located in the small intestine. Accordingto some embodiments, identifying the target area is performed before theadvancing step. According to some embodiments, the distal end of thelaser emitting catheter is advanced into the duodenum, and wherein thewall of the small intestine comprises a duodenal wall.

According to some embodiments, the method further comprises repeating atleast the emitting step to damage more than one sensory nerve at thetarget area or at a different target area. According to someembodiments, emitting the focused laser beam comprises directing thebeam with a rotatable optical element coupled with the laser emittingcatheter. According to some embodiments, directing the beam comprisesangling the beam so that it passes through an aperture on a side of thecatheter. According to some embodiments, the method further comprisessplitting the beam into two beams, wherein a first beam of the two beamsis directed at the target area.

According to another aspect, the present disclosure provides a systemfor use in blocking at least part of neural activity in at least oneneural region in an organ of a subject in need thereof, the systemcomprising:

-   -   a catheter for blocking at least part of the neural activity in        the organ of a subject in need thereof, the catheter comprising:    -   an elongate catheter body having a proximal end and a distal        end;    -   a laser emitting element coupled with the catheter body at or        near the distal end and configured to emit a focused laser beam;        and    -   a scanning optical element coupled with the laser emitting        element and configured to direct the focused laser beam to one        or more target areas on or beneath a wall of the organ, wherein        the target area comprises at least one sensory nerve, such that        the laser beam is configured to cause damage to the at least one        sensory nerve.

According to some embodiments, the scanning of the laser targets avein-artery-nerve (VAN) interface with a duodenum to elevate temperatureand induce injury in nerves. According to some embodiments, the scanningoptical element enables deflection of light of one of: (i) a lineparallel to a lumen axis; (ii) around a lumen axis. According to someembodiments, the laser radiation comprises a wavelength configured to bestrongly absorbed by a pigment inserted to enhance absorption at thetarget area.

According to another aspect, the present disclosure provides a methodfor reducing or blocking at least part of the neural activity in anorgan of a subject in need thereof, the method comprising:

-   -   introducing at least one light emitting element device into the        organ;    -   actuating said light emitting element to activate a        photosensitizer to induce injury at a target area on or beneath,        within or in contact with at least part of a wall of the organ        and thereby damage at least one sensory nerve located at the        target area to at least partially reduce the neural activity.

Further embodiments, features, advantages and the full scope ofapplicability of the present invention will become apparent from thedetailed description and drawings given hereinafter. However, it shouldbe understood that the detailed description, while indicating preferredembodiments of the invention, are given by way of illustration only,since various changes and modifications within the spirit and scope ofthe invention will become apparent to those skilled in the art from thisdetailed description.

BRIEF DESCRIPTION OF THE FIGURES

Exemplary embodiments are illustrated m referenced figures. Dimensionsof components and features shown in the figures are generally chosen forconvenience and clarity of presentation and are not necessarily shown toscale. It is intended that the embodiments and figures disclosed hereinare to be considered illustrative rather than restrictive. The figuresare listed below.

FIG. 1A schematically illustrates a section of a duodenum, depictingvarious layers of the duodenal wall.

FIG. 1B schematically illustrates a lateral cross section through aduodenum, depicting various layers of the duodenal wall.

FIG. 2A schematically illustrates a catheter, which 1s inserted into thelumen of the duodenum, according to some embodiments.

FIG. 2B schematically illustrates an endoluminal duodenal catheter,which emits a laser beam, according to certain embodiments.

FIG. 2C schematically illustrates a longitudinal cross section through acatheter, according to certain embodiments.

FIG. 2D schematically illustrates a longitudinal cross section through acatheter, according to certain embodiments.

FIG. 3A schematically illustrates a longitudinal cross section throughpart of a duodenum and a catheter inserted within the lumen of theduodenum, according to some embodiments.

FIG. 3B schematically illustrates a longitudinal cross section throughpart of a catheter, according to certain embodiments.

FIG. 4 schematically illustrates a longitudinal cross section throughpart of a duodenum and a catheter inserted within the lumen of theduodenum, according to some embodiments.

FIG. 5A schematically illustrates, according to some embodiments, acatheter which is inserted into the lumen of a duodenum comprising alaser element and deflated balloons.

FIG. 5B schematically illustrates, according to some embodiments, acatheter which is inserted into the lumen of a duodenum comprising alaser element and inflated balloons which exert pressure on the duodenalwall.

FIG. 6 schematically illustrates an endoluminal duodenal catheter, whichemits a laser beam, according to some embodiments.

FIG. 7 schematically illustrates an alternative embodiment that uses alaser that is absorbed by the tissue, but the beam is focused to thetargeted layer

FIG. 8 schematically illustrates an embodiment of the endoluminalduodenal catheter of FIG. 6 showing the lens and its ability to splitthe laser beam.

FIG. 9 schematically illustrates an endoscope having a catheterassembled on the endoscope.

DETAILED DESCRIPTION

In the following description, various aspects of the disclosure will bedescribed. For the purpose of explanation, specific configurations anddetails are set forth in order to provide a thorough understanding ofthe different aspects of the disclosure. However, it will also beapparent to one skilled in the art that the disclosure may be practicedwithout specific details being presented herein. Furthermore, well-knownfeatures may be omitted or simplified in order not to obscure thedisclosure.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates, as used herein, mean “including but not limitedto”. The terms “comprises” and “comprising” are limited in someembodiments to “consists” and “consisting”, respectively. The term“consisting of” means “including and limited to”. The term “consistingessentially of” means that the composition, method or structure mayinclude additional ingredients, steps and/or parts, but only if theadditional ingredients, steps and/or parts do not materially alter thebasic and novel characteristics of the claimed composition, method orstructure. In the description and claims of the application, each of thewords “comprise” “include” and “have”, and forms thereof, are notnecessarily limited to members in a list with which the words may beassociated.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

As used herein the term “about” refers to plus/minus 10% of the valuestated. As used herein, the term “plurality” refers to at least two.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, may alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the disclosure, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the disclosure. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

The disclosure incorporates herein by reference in their entirety U.S.Provisional Patent Nos. 61/758,816 and 61/835,597, both entitled“ENDOLUMINAL INTERVENTIONS FOR MANAGEMENT OF TYPE 2 DIABETES, INSULINRESISTANCE AND OBESITY”, filed on Jan. 31, 2013 and Jun. 16, 2013,respectively.

According to one aspect, the present disclosure provides a method forblocking at least part of the neural activity in an organ of a subjectin need thereof, the method comprising:

-   -   introducing at least one laser element into the organ; actuating        the laser element to emit laser radiation;    -   focusing the laser radiation to a target area within or in        contact with at least part of a wall of the organ, wherein the        target area comprises sensory nerves, such that the radiation is        configured to cause damage to at least part of the sensory        nerves. According to some embodiments, the organ is a small        intestine or duodenum.

According to some embodiments, the wall of the organ is the wall of theduodenum or the duodenal wall.

According to some embodiments, functional activity of tissue surroundingthe sensory nerves 1s maintained, despite damage being caused to the atleast part of the sensory nerves.

I. Biological Definitions

As used herein, the term “duodenum” refers to the part of the smallintestine of a vertebrate's gastrointestinal tract which is situatedbetween the stomach and the jejunum. According to some embodiments, theduodenum comprises the pylorus of the stomach. According to someembodiments, the pylorus of the stomach comprises at least one of: thepyloric antrum, the pyloric canal and a combination thereof. Eachpossibility represents a separate embodiment of the present disclosure.According to some embodiments, the duodenum comprises theduodenal-jejunal junction. According to some embodiments, the duodenumcomprises the lumen and the duodenal wall surrounding the lumen. As usedherein, the terms “duodenal wall” and “wall of the duodenum” are usedinterchangeably

According to some embodiments, the duodenal wall comprises the followinglayers from the lumen outwards: the mucosa villi layer, the submucosalayer which comprises the submucosal plexus, the circular muscle layer,the myentric plexus, the longitudinal muscle layer and theperitoneum/mesenteric layer. According to some embodiments, thecombination of the circular muscle layer and longitudinal muscle layeris referred to herein as the tunica muscularis.

According to some embodiments, the terms “submucosal plexus” and“Meissner's plexus” are used interchangeably and refer to a neuralplexus residing in the submucosa layer of the duodenal wall. Accordingto some embodiments, the submucosal plexus transmits neural signalswithin the duodenum. According to some embodiments, the submucosalplexus transmits neural signals to nerves extrinsic to the duodenum,such as, but not limited to the vagus, duodenal ganglia, sympatheticnerves, parasympathetic nerves and a combination thereof. Eachpossibility represents a separate embodiment of the present disclosure.According to some embodiments, the submucosal plexus comprises mainlysensory neurons. According to some embodiments, the submucosal plexustransmits neural signals resulting from activity of chemical and/ormechanical sensors in the duodenum. Each possibility represents aseparate embodiment of the present disclosure. According to someembodiments, the submucosal plexus transmits neural signals resultingfrom activity of chemical and/or mechanical sensors in the duodenumwhich are configured to be activated by passage of food through theduodenum. Each possibility represents a separate embodiment of thepresent disclosure.

According to some embodiments, the terms “Auerbach's plexus” and“Myentric plexus” are used interchangeably and refer to a neural plexusresiding in the tunica muscularis of the duodenal wall. According tosome embodiments, signals from mechano-sensors and/or chemo-receptors inthe duodenal wall which are induced by passage of food through theduodenum pass through the Myentric plexus.

Reference is now made to Figure IA, showing a schematic representationof section (100) through part of a duodenum, depicting the variouslayers of the duodenal wall according to some embodiments. Lumen (102)is surrounded by mucosa (104), which in turn is surrounded by submucosalayer (106). Submucosa layer (106) comprises submucosal plexus (108).Submocosal plexus (108) innervates nerves (124 a, 124 b, 124 c, 124 d,124 e and 124 f) which are part of vein, arteries and nerves (VAN)arrays (122 a, 122 b, 122 c, 122 d, 122 e and 122 f), respectively,present in mesenteric layer (120) of the duodenal wall. According tosome embodiments, nerves (124 a, 124 b, 124 c, 124 d, 124 e and 124 f)transfer signals outside of the duodenum to nerves such as, but notlimited to, vagal nerves, sympathetic nerves, parasympathetic nerves ora combination thereof. Blood vessels of VAN (vein, arteries and nerves)arrays (122 a, 122 b, 122 c, 122 d, 122 e and 122 f) are connected toblood vessels (110) in the duodenal wall. Circular muscle layer (112)surrounds submucosa layer (106). Myentric plexus (116) is present inintermuscular stroma (114) which resides between circular muscle (112)and longitudinal muscle (118). Longitudinal muscle (118) is surroundedby mesenteric/peritoneum layer (120). Figure IB depicts a cross sectionthrough duodenum section (100), showing lumen (102), mucosa (104),submucosa layer (106) which comprises submucosal plexus (108), circularmuscle (112), Myentric plexus (116), longitudinal muscle (118) andmesenteric/peritoneum layer (120).

According to some embodiments, blocking at least part of the neuralactivity in an organ, such as a duodenum, refers to blocking at leastpart of the neural activity in sensory neurons of the organ. Accordingto some embodiments, blocking at least part of the neural activity in aduodenum refers to blocking neural activity in at least one target area.According to some embodiments, blocking at least part of the neuralactivity in a duodenum refers to blocking sensory neural activity in atleast one target area. According to some embodiments, blocking at leastpart of the neural activity in a duodenum refers to blocking at leastpart of the neural activity in response to passage of food through theduodenum. According to some embodiments, blocking at least part of theneural activity in a duodenum refers to blocking at least part of theneural activity in sensory neurons in response to passage of foodthrough the duodenum. According to some embodiments, passage of foodthrough the duodenum induces neural activity in the duodenum. Accordingto some embodiments, passage of food through the duodenum inducesactivity of sensory neurons in the duodenum. According to someembodiments, passage of food through the duodenum induces neuralactivity in the duodenum as a response to signals triggered by the foodpassage, such as, but not limited to, neurohormonal signals, signalsreceived from mechano-sensors, signals received from chemo-sensors and acombination thereof. Each possibility represents a separate embodimentof the present disclosure.

According to some embodiments, blocking neural activity in a target arearefers to at least one of: reducing neural conductance within at leastsome neurons in the target area, abrogating neural conductance within atleast some neurons in the target area, reducing neural conductancewithin at least some synapses in the target area, abrogating neuralconductance within at least some synapses in the target area or acombination thereof. Each possibility represents a separate embodimentof the present disclosure. As used herein, the terms “neuron” and“nerve” are used interchangeably.

According to some embodiments, a target area is an area that containssensory neurons which resides within a duodenal wall or in contact withat least part of a duodenal wall. According to some embodiments, thetarget area resides within at least one layer of the duodenal wall.According to some embodiments, the target area resides at the interfacebetween duodenal wall and sensory nerves that are configured to transmitneural signals out of the duodenum, such as, but not limited to, neuronsin VAN (vein, arteries and nerves) arrays. According to someembodiments, a target area comprises sensory neurons configured totransmit internal neural signals within the duodenum. According to someembodiments, a target area comprises sensory neurons configured totransfer signals between neural plexuses and/or chemical/mechanicalsensors within the duodenal wall. Each possibility represents a separateembodiment of the present disclosure. According to some embodiments, atarget area comprises sensory neurons configured to transmit neuralsignals outside of the duodenum to various ganglia and/or nerves suchas, but not limited to, vagal nerves and/or various sympathetic and/orparasympathetic nerves. Each possibility represents a separateembodiment of the present disclosure.

According to some embodiments, a target area comprises sensory neuronsconfigured to transmit signals in response to passage of food throughthe duodenum. As used herein, the term “sensory neurons” relates toneurons configured to transmit neural stimuli corresponding to sensorystimuli. According to some embodiments, sensory neurons are activated byphysical and/or chemical stimuli, such as, but not limited to,mechano-sensors and/or chemo-receptors on the duodenal wall. Eachpossibility represents a separate embodiment of the present disclosure.According to some embodiments, sensory neurons within a target area inthe disclosed method relates to sensory neurons configured to transmitsensory stimuli induced by passage of food through the duodenum. As usedherein, the term “motor neurons” relates to neurons configured to inducemuscle movement, either directly or indirectly.

According to some embodiments, a target area comprises sensory neuronsconfigured to transmit signals in response to signals received frommechano-sensors and/or chemo-receptors within the duodenal wall. Eachpossibility represents a separate embodiment of the present disclosure.According to some embodiments, a target area comprises sensory neuronsconfigured to transmit signals in response to signals received frommechano-sensors and/or chemo-receptors within the duodenal wall inresponse to food passage through the duodenum. Each possibilityrepresents a separate embodiment of the present disclosure.

According to some embodiments, the target area comprises at least partof the myentric plexus, the submucosal plexus or a combination thereof.Each possibility represents a separate embodiment of the presentdisclosure. According to some embodiments, the target area comprises atleast part of the submucosal plexus. According to some embodiments, thetarget area comprises at least part of the neurons within VAN arrayspresent in the mesenteric layer of the duodenal wall. According to someembodiments, the target area comprises at least part of the neuronsconnecting the duodenum to VAN arrays present in the mesenteric layer ofthe duodenal wall.

According to some embodiments, the target area comprises at least partof the neurons within regions selected from the group consisting of: themyentric plexus, the submucosal plexus, duodenal branches of the vagusnerve, sympathetic nerves innervating the duodenal wall, parasympatheticnerves innervating the duodenal wall, VAN arrays in the duodenal walland a combination thereof. Each possibility represents a separateembodiment of the present disclosure. According to some embodiments, thetarget area comprises the anterior (left) vagal nerve. According to someembodiments, the target area comprises the interface of the anterior(left) vagal nerve with the duodenum. According to some embodiments, thetarget area comprises at least part of the hepatic branch of the leftvagal nerve and/or at least part of the gastroduodenal branch of thevagal nerve. Each possibility represents a separate embodiment of thepresent disclosure.

According to some embodiments, a target area may further comprise motorneurons. According to some embodiments, a target area within theMyentric plexus may further comprise motor neurons. Without wishing tobe bound by any theory or mechanism, motor neurons may be able toregenerate following damage, thus induction of damage to sensory neuronswithin a target area while maintaining functional activity of motorneurons within the target area is enabled.

II Laser Element and Catheter

According to some embodiments, the disclosed method comprisesintroduction of at least one laser element into an organ, such as thelumen of a subject's duodenum. According to some embodiments, a laserelement is an element configured to emit laser radiation. According tosome embodiments, a laser element refers to an optomechanic systemconfigured to deliver laser radiation. As used herein, the terms laserelement, optomechanic system and optomechanical head are usedinterchangeably. According to some embodiments, a laser element is anelement configured to emit focused laser radiation. According to someembodiments, the laser element is comprised in, and possibly locatedwithin, a catheter. Each possibility represents a separate embodiment ofthe present disclosure. According to some embodiments, the laser elementis attached to a catheter. According to some embodiments, a laser isconnected to the catheter and/or laser element through at least oneoptical fiber. According to some embodiments, the optomechanical head isintroduced into the lumen of a subject's duodenum by using a catheter.According to some embodiments, the optomechanical head is introducedinto the lumen of a subject's duodenum by using an endoscope. As usedherein, the terms “catheter” and “endoluminal duodenal catheter” areused interchangeably and refer to a catheter which is configured to beintroduced into the lumen of a duodenum. According to some embodiments,the catheter is configured to be introduced into the lumen of a duodenumthrough the mouth of a subject. According to some embodiments, thecatheter is configured to be introduced through the colon. According tosome embodiments, the catheter has a proximal region and a distalregion. In certain embodiments, the distal region has one or moreapertures. According to some embodiments, the distal region of thecatheter has a larger diameter than the proximal region of the catheter.According to some embodiments, the distal region is made of a differentmaterial than the proximal region of the catheter, such as, but notlimited to including a hydrophilic coating

According to some embodiments, a laser element comprises at least oneoptic fiber. According to some embodiments, a laser element comprises atleast part of an optic fiber. According to some embodiments, the opticfiber is configured to emit laser radiation. According to someembodiments, the optic fiber is functionally connected to a lasersource. According to some embodiments, the laser element is functionallyconnected to a laser source. According to some embodiments, the laserelement comprises the laser source. According to some embodiments, thelaser source is external to the subject to which the laser element isinserted.

According to some embodiments, the laser element comprises a rotatableoptical element. According to some embodiments, the rotatable opticalelement is a rotatable prism. According to some embodiments, therotatable optical element is a rotatable mirror. According to someembodiments, the rotatable optical element is a rotatable beam splitter.According to some embodiments, the rotatable optical element is locatedin the distal region of the catheter.

Reference is now made to FIG. 2A depicting use of the disclosed method,system and apparatus, according to some embodiments. Catheter (218A)which comprises laser element (220A) is introduced into lumen (216) ofduodenum (200). Laser element (220A) emits focused laser radiation(224A) through optical window (222A). Laser radiation (224A) crossesmucosal layer (214) and is focused on submucosa layer (210) to targetsubmucosal plexus (212). According to some embodiments laser element(220A) which may be an optomocechanical head, is configured to targetsubmucosal plexus (212). According to certain embodiments selectivetargeting is achieved by using chemical substances that bind to elementsof the neural system. According to other embodiments, laser element(220A) may emit laser radiation focused on part on the tunica muscularislayers such as circular muscle (208) and longitudinal muscle layer(204). According to other embodiments, laser element (220A) may emitlaser radiation focused on part of myentric plexus (206) residingbetween circular muscle (208) and longitudinal muscle layer (204).According to certain embodiments, laser element (220A) may emit laserradiation focused on a target area in mesentry layer (202) comprisingsensory neurons which innervate the duodenal wall. According to someembodiments, the laser radiation may be in the form of a line focused ona target area or a spot scanned across the interface area in mesentrylayer (202) comprising sensory neurons which innervate the duodenalwall. According to certain embodiments, laser element (220A) may emitlaser radiation focused on a target area on other areas within the lumen(216) of duodenum (200).

FIG. 2B illustrates an endoluminal duodenal catheter according to someembodiments. Catheter (218B) comprises laser element (220B), which emitslaser radiation (224B) through aperture (222B). According to someembodiments, laser radiation (224B) has angle (0) relatively to catheter(218B). According to some embodiments, angle (0) may be 90 degrees, orhave an acute or obtuse angle configured to deliver laser radiation(224B) to a desired target area. According to some embodiments, laserelement (220B) is rotatable, such that laser radiation (224B) may befocused to a plurality of target areas within a substantially circulartrajectory. According to some embodiments, laser element (220B) isrotatable around longitudinal axis (236) of catheter (218B). Accordingto some embodiments, an actuator is used to rotate the laser element.According to some embodiments, rotation angle (238) of laser element(220B) may be, but is not limited to, 0, 30, 45, 70, 90, 120, 150, 180or 360 degrees around longitudinal axis (236) of catheter (218B). Eachpossibility represents a separate embodiment of the present disclosure.

FIG. 2C illustrates a longitudinal cross section through the endoluminalduodenal catheter illustrated in FIG. 2B. Catheter (218C) comprisesoptomechanical head (220C) and optic fiber (226). According to someembodiments, optic fiber (226) is functionally. connected to a lasersource. Optic fiber (226) is at least partly comprised withinoptomechanical head (220C) and emits laser radiation (228). Laserradiation (228) is directed at rotatable prism (234) which deflectslaser radiation (228) to laser radiation (224C). Although rotatableprism (234) is depicted as a triangular prism it is to be noted that anysuitable shape may be used, such as, but not limited to, pyramidal,hexagonal or cuboidal. Other such prisms, or any other associated prismsor lens elements known in the art may be used. Additional detail isprovided below in Section VIII regarding optical lens systems.

As shown, laser radiation (224C) exits optomechanical head (220C)through optical window (222C) and is directed towards a target areawithin the duodenal wall. According to some embodiments, optical window(222C) is an aperture. According to other embodiments, the walls ofcatheter (218C) are transparent, obviating the need for an aperture oroptical window. According to some embodiments, more than one aperture islocated in the walls of the catheter (218C). According to someembodiments, optical window (222C) may be located at an angle and/orposition which allows laser radiation (224C) to exit optomechanical head(220C).

FIG. 2D illustrates a longitudinal cross section through an endoluminalduodenal catheter, according to certain embodiments of the presentdisclosure. Catheter (218D) comprises laser element (220D) and opticfiber (226A). According to some embodiments, optic fiber (226A) emitslaser radiation (224D) through lens (240) towards reflecting beamsplitter (234D). Laser radiation (224D) passes through lens (248) andoptical window (222D) towards a target area. According to someembodiments, reflecting beam splitter (234D) is a partially reflectivemirror configured to enable some of the laser radiation reflected backfrom the target area and/or some of the scattered radiation to passthrough lens (242) and be collected by imaging element (246). Imagingelement (246) may be any suitable element for capturing informationabout the structure of the duodenum and/or surrounding tissue. Accordingto some embodiments, imaging element (246) is configured to enabledetermining whether laser beam (224D) is focused on the desired targetarea and/or monitoring the irradiation process in real time. Eachpossibility represents a separate embodiment of the present disclosure.According to some embodiments, laser element (220D) includes means torotate around the longitudinal axis of catheter (218D) together withlenses (240,242), reflecting beam splitter (234D) and imaging element(246). According to some embodiments, imaging element (246) may comprisesingle or multiple detectors such as CMOS and/or CCD. According to someembodiments, imaging element (246) is not configured to rotate and canenable imaging only during part of the rotation around the longitudinalaxis of catheter (218D). Non-limiting examples of imaging elements, maybe, but not limited to a liner array camera or an array detector that isstationary and surrounds catheter (218D) such as a CCD or a CMOS chipliner array. According to some embodiments, imaging element (246)includes or is functionally connected to a processor or a controller tocontrol and process information about the structure of the duodenumand/or surrounding tissue. According to some embodiments, the processoror controller is configured to process information regarding changes intarget area characteristics upon interaction with the laser beam.According to some embodiments the optical path used for focusing may beused for imaging if required, such as, but not limited to, using theconfocal optics principle. Alternatively, a different optical path maybe used for focusing laser radiation at a target area and imaging.According to non-limiting examples, imaging may be performed usingtechnologies such as, but not limited to, Near Infra-Red (NIR), visibledirect of fluorescence based optical imaging, ultrasound based imaging,photoacoustic microscopy, Optical Coherence Tomography (OCT) basedimaging or any combination thereof. According to some embodiments, forimplementation of photoacoustic imaging/microscopy that is based on thephotoacoustic effect in which the pulse energy induces an acoustic wavethat is sensitive to laser energy absorption and mechanicalcharacteristics of the tissue, at least one acoustic transducer isattached to the catheter with direct or semi-direct contact with thetissue or through interface through liquid. Each possibility representsa separate embodiment of the present disclosure.

III. Laser Element and Types of Laser Radiation

According to some embodiments, the disclosed method comprises focusinglaser radiation to a target area within or in contact with at least partof an organ of a subject, such as a subject's duodenum and/or duodenalwall to selectively ablate and/or damage neurons, such as, but notlimited to sensory nerves including, but not limited to sensory nervesin the submucosal plexus or the myentric plexus of the duodenum. Eachpossibility represents a separate embodiment of the present disclosure.

According to some embodiments, the laser radiation is laser radiationnot configured to be significantly absorbed in a tissue of an organ of asubject, such as a subject's duodenum. According to some embodiments,laser radiation not configured to be absorbed in tissue outside thetarget area may pass through at least one layer of the duodenum on itsway to the target area without causing damage to the at least one layerof the duodenum. In a non-limiting example, laser radiation notconfigured to be significantly absorbed in tissue outside the targetarea which is directed at a target area within the submucosal layer ofthe duodenum may traverse through the mucosal layer of the duodenumwithout damaging it.

According to some embodiments, laser radiation not configured to beabsorbed in tissue outside the target area is laser radiation configuredto induce an energy peak sufficient to cross a fluence threshold todamage a tissue or initiate a process leading to damage only within thetarget area. Each possibility represents a separate embodiment of thepresent disclosure. According to some embodiments, laser radiation notconfigured to be absorbed in tissue outside the target area is selectedfrom the group consisting of: pulsed laser or CW laser or Quasi CWradiation in Near Infra-Red (NIR) or visible spectrum and a combinationthereof. Each possibility represents a separate embodiment of thepresent disclosure. According to some embodiments, NIR laser radiationis typically in the range of 700-1350 nm. According to some embodiments,the laser radiation is typically in the range of 700-1350 nm. Accordingto some embodiments, the laser radiation is in a range selected from thegroup consisting of: 700-900 nm, 700-1100 nm, 1000-1350 nm and 1000-1200nm. Each possibility represents a separate embodiment of the presentdisclosure. According to a non-limiting example, a suitable NIR laserradiation is produced by a pulsed neodymium-doped yttrium aluminumgarnet (Nd:YAG) laser emitting radiation at a wavelength of 1064 nm.

According to some embodiments, the laser radiation is a pulsed laserradiation to initiate non-linear based interaction processes andnon-linear energy absorption and interaction with the tissue. Withoutwishing to be bound by any theory or mechanism, short pulsed focusedlaser directed at a tissue may result in a non-linear interaction withthe tissue such that plasma formation and/or photo-ablation occur onlyat a site in the tissue in which the energy peak at a given area has anenergy flux high enough to cross a pre-determined threshold. Accordingto some embodiments, photo-ablation in the presence of a high enoughpeak power in the focus area may be accompanied with some level, even ifsmall, of absorption of the laser beam by the tissue. By this means,laser that is not absorbed or not strongly absorbed by the tissue mightbe used so that high energy is not significantly impacting the mucosallayer so as to not cross the flux threshold in areas on which the beamis not focused.

According to some embodiments, focused pulsed laser is configured not tobe absorbed in tissue outside of the target area of the laser. Accordingto some embodiments, focused pulsed laser is configured not to besignificantly absorbed in tissue outside of the target area of thelaser. According to some embodiments, significant absorbance of laserradiation in a tissue is absorbance configured to cause damage to thetissue. By mode of example, Q Switched Nd:YAG laser can be used toinitiate damage at flux in the order of 50-250 mJ/mm2 using laser at1064 nm with 5-10 nsec pulses. According to other embodiments, fluxes of25-75 mJ/mm2 may be employed if a second harmonic 532 nm laser is used.This flux may be lower as the absorption in the tissue is significantlyhigher. Without wishing to be bound by any theory or mechanism, theselevels of fluxes with the abovementioned lasers are able to cross athreshold of ablation that leads to chemical and/or mechanicaldistribution of the tissue and can cause direct or induced damage of thetarget area. Alternatively, lower fluxes may be used with shorter pulsesthat induce plasma formation in the target area even when the absorptionis very low. This may lower the threshold fluence by more than an orderof magnitude depending on the pulse width and be in the range of 1mJ/mm2 with fsec pulses even when the linear absorption is negligible(Alexander A. Oraevsky et al, IEEE JOURNAL OF SELECTED TOPICS IN QUANTUMELECTRONICS, VOL. 2, NO. 4, DECEMBER 1996). A laser beam that passesthrough a tissue below these fluence thresholds, according to someembodiments, will not initiate the non-linear realted damages effectsand will minimize impact and damage to tissue outside the target area,on which the laser is not focused.

According to some embodiments, focused pulsed laser is minimallylinearly absorbed in tissue outside of the target area of the laser.According to some embodiments, focused pulsed laser is minimallyabsorbed in tissue outside of the target area of the laser such thattissue outside the target area is not damaged. According to someembodiments, focused pulsed laser is minimally absorbed in tissueoutside of the target area of the laser such that tissue outside thetarget area maintains functional activity. According to someembodiments, using a pulsed laser prevents absorption or inducednon-significant absorption of laser radiation in the mucosa and/ortunica muscularis of the duodenal wall. Each possibility represents aseparate embodiment of the present disclosure. Non-limiting examples oflasers that may be used to produce such laser radiation include microQ-Switched Nd:YAG lasers such as, but not limited to, those manufacturedby Kigre (MK-367) that are very compact and produce a beam that maycross ablation threshold when sufficiently focused, standard flashpumped Q-Switched lasers (including those that are self Q-Switched),high repetition rate Solid Sate Diode Pumped Nd:YAG lasers, fiber laserswhich use small spots to obtain a high enough peak power to cause damageor any combination thereof. Each possibility represents a separateembodiment of the present disclosure. Other non-limiting examplesinclude CW, quasi CW or Q switched lasers. Appropriate lasers can be,for example, double YAG in 532 nm, or laser diode m 980 nm 808 nm, alaser in the 1,500 nm range or Holmium/Thuliium lasers at ˜2 microns.

According to some embodiments, focused pulsed laser is partiallylinearly absorbed in tissue outside of the target but the flux is higherat the target to elevate the temperature of tissue upon laser beamabsorption to a higher temperature in the focus target area compared tothe non-focus area.

Reference is now made to FIG. 3A, illustrating, according to someembodiments, blocking of neural activity in the duodenal wall by use oflaser radiation which is not configured to be significantly linearlyabsorbed in tissue outside the target area. FIG. 3A depicts alongitudinal cross section through part of duodenum (300) and catheter(316) which is introduced into the lumen of duodenum (300). The duodenumwall of duodenum (300) comprises the mucosal layer (302A, 302B), thesubmucosal layer (304A, 304B) which comprises submucosal plexus (306Aand 306B, respectively), circular muscle (308A, 308B), myentric plexus(310A, 310B), longitudinal muscle (312A, 312B) and mesenteric layer(314A, 314B).

Catheter (316) comprises laser element (318) and optic fiber (320) whichis partially comprised in laser element (318). Optic fiber (320) emitslaser radiation (322A, 322B) which passes through collimating lens (330)and is then rotated by rotatable prism (324) and focused by focusinglens (332) such that focused laser radiation (326) is directed at targetarea (328). Target area (328) in the duodenal wall comprises part of thesensory neurons of submucosal plexus (306A). According to someembodiments, focusing lens (332) is configured to rotate together withthe rotatable prism (324) and/or other means of reflection. According tosome embodiments, collimating lens (330) is rotatable and is optionallypart of the rotating laser element (318). According to some embodiments,laser element (318) further comprises at least one focusing element,such as, but not limited to, at least one lens (332), configured tofocus laser radiation (326) at target area (328). According to someembodiments, the at least one focusing element is able to focus thelaser radiation (326) at different angles, including, but not limitedto, 0, 30, 45, 70, or 90 degrees from the longitudinal axis of thecatheter (316), such that the laser radiation is configured to bedirected at the desired target area.

According to some embodiments, laser radiation (326) is non-uniform suchthat the energy level of laser radiation (326) is the highest at targetarea (328) on which it is focused. According to some embodiments, laserradiation (326) is configured to induce nonlinear interaction with thetissue, such that the energy level of laser radiation (326) is only highenough to induce damage within target area (328) on which it is focusedand not in surrounding tissue. Laser radiation (326) is laser radiationconfigured not to be absorbed or to be non-significantly absorbed intissue. According to some embodiments, lens (332) is placed on atranslator to enable control of focal plane. A typical focal length maybe in the range of 2-25 mm, depending on the configuration. According tosome embodiments, a typical beam diameter (334) of laser radiation(322A, 322B) is in the range of 1-20 mm. By mode of example, if a 5 mmcollimated beam is obtained using collimating lens (330) for collimationof a Gaussian shape beam exiting from optic fiber (320), and a 15 mmfocal lens is used as focusing lens (332), a spot in the range of 10microns may be formed (depending on aberrations and scattering) with afocus depth in the range of tens of microns, thereby enabling localizeddamage. Each possibility represents a separate embodiment of the presentdisclosure.

According to some embodiments, laser radiation (326) is pulsed laser,quasi CW or CW laser or a combination thereof. Each possibilityrepresents a separate embodiment of the present disclosure. According tosome embodiments, laser radiation (326) is configured to induce damageonly within target area (328) and to induce no damage or non-significantdamage to mucosa (302A) which it passes in order to get to target area(328) and to duodenal layers (310A, 312A, 314A) which it passes afterhaving arrived at target area (328). Each possibility represents aseparate embodiment of the present disclosure.

According to some embodiments, laser radiation (326) is focused ontarget area (328) or, in some embodiments, its anatomical area (304A)and thus laser radiation (326) crosses the ablation threshold onlywithin target area (328) or (304A), respectively. Each possibilityrepresents a separate embodiment of the present disclosure.

According to some embodiments, laser radiation (326) is configured tohave enough linear optical absorption to elevate tissue temperature uponabsorption and yet not to be absorbed strongly at the surface to enablelarge enough penetration depth. By mode of example, a 808CW laser beammay be used as it is partially absorbed in a tissue but can effectivelypenetrate a few mm. Laser beam in the range of a 100 mW-10 Watts,depending on the spot size and illumination length, may be used toelevate the tissue temperature at the focal plane to a pre-determinedthermal window such as 45-75 Celsius degrees. According to someembodiments, laser radiation (326) is focused on target area (328) andthus induces temperature elevation which results in thermal induceddamage only within target area (328).

According to some embodiments, rotatable prism (324) and/or laserelement (318) are configured to rotate and enable direction of laserradiation (326) to other target areas, such as, but not limited to atarget area comprising part of the sensory neurons of submucosal plexus(306B). Each possibility represents a separate embodiment of the presentdisclosure.

According to some embodiments, rotatable prism (324) and/or laserelement (318) are configured to rotate and enable direction of laserradiation (326) to several target areas, such as, but not limited to, atarget area comprising part of the sensory and/or motility neurons intunica muscularis layers such as myentric plexus (310B). Eachpossibility represents a separate embodiment of the present disclosure.

According to some embodiments, the laser radiation is configured to befocused on the target area via at least one aperture located in the wallof the catheter (316). According to some embodiments, the laserradiation is absorbable in the target area and tissue surrounding thetarget area. According to some embodiments, the laser radiation isfocused on the target area such that it induces its main damage in thetarget area while minimizing its collateral impact on layers surroundingthe target area.

According to some embodiments, the absorbable laser radiation isproduced by a laser source selected from the group consisting of:continuous-wave (CW) laser, quasi continuous-wave laser, Q-switchedlaser and a combination thereof. Each possibility represents a separateembodiment of the present disclosure. According to non-limitingexamples, the laser radiation is produced by a laser selected from thegroup consisting of: a double YAG laser emitting radiation at awavelength of 532 nm, a laser diode emitting radiation at a wavelengthof 808 nm-980 nm, a laser diode emitting radiation at a wavelength of1500 nm, a 2 microns Holmium Thuliium and a combination thereof. Eachpossibility represents a separate embodiment of the present disclosure.

According to some embodiments, the laser radiation is high power 808 nmradiation. According to some embodiments, a high power laser radiationsuch as an 808 nm radiation is configured to enable targeting a shapesuch as a longitudinal line across the duodenum simultaneously.According to the embodiment illustrated in FIG. 3B, targeting a shapesuch as a longitudinal line across the duodenum simultaneously may beachieved by passing laser radiation through cylindrical lens (332′)directing laser radiation (226′) at target area (328′). According tosome embodiments, targeting a shape such as a longitudinal line acrossthe duodenum simultaneously is directed at a focal plane in theperipheral wall of the duodenal wall to target interface of the duodenumwith ganglia and/or vagal nerves and/or the VAN interface. Eachpossibility represents a separate embodiment of the present disclosure.Of note, other than cylindrical lens (332′) and laser radiation (226′),all elements in FIG. 3B correspond to elements in FIG. 3A.

According to some embodiments, such laser radiation produced by a lasersource such as CW or quasi CW or pulsed laser may be focused on theouter layers of the duodenal wall using optics. Alternatively, this canbe done by using a focused beam longitudinally which is moved in a linepattern across the duodenum or by moving the laser element across theduodenum. According to other embodiments, a line spot may be focused onthe target area and rotated around the lumen axis by using a cylindricallens, as exemplified in FIG. 3B in which cylindrical lens (332′) isfocused on a focal plane parallel to the rotation axis. Each possibilityrepresents a separate embodiment of the present disclosure. According tosome embodiments, a laser such as a high power 808 nm laser might beused that so as to enable the exposure of a longitudinal line across theduodenum simultaneously; such as, the use of CW or quasi CWillumination; wherein optics is used to focus the beam at the outersection of the duodenum wall.

According to another embodiment, the laser radiation is produced by alaser that is coupled to a series of fibers (which form a bundle)illuminating at different length or using cylindrical diffusing fibers(such as MedLight Cylindrical light diffuser Model RD) combined with areflector and cylindrical lens to get illumination in part of a circle.Embodiments based on such a fibers can be used also in combination withprevious embodiments to create a circle like impact or to create aspiral or helical like impact. In another embodiment an array of laserdiodes can be used to simultaneously direct laser radiation to thetarget area.

According to some embodiments, the damage induced by the laser radiationat the target area is higher than that induced in its surrounding.Without wishing to be bound by any theory or mechanism, the damageinduced by the laser radiation at the target area is higher than thatinduced in its surrounding due to a higher temperature elevation at thetarget area. According to some embodiments, the damage induced by thefocused laser radiation in its optical path is smaller than the damageinduced at the focal plane of the focused laser radiation. According tosome embodiments, the damage induced by the laser radiation at thetarget area is higher than that induced in its surrounding despiteintensity attenuation and/or absorption and/or scattering of the laserradiation. Each possibility represents a separate embodiment of thepresent disclosure. According to some embodiments, the focal plane ofthe focused laser radiation is at the target area of the laserradiation.

In yet another embodiment, a 2.9 laser with free running pulses rangingfrom micro-hundreds of seconds to micro-seconds (such as 3Mikron Er:YAGlasers) or a pico-sec (such as PIRL manufactured by Attodyne Lasers) ornano-sec laser can be used to generate very thin controlled cuts in theduodenal wall by ablation. Controlled cuts may be performed with otherlasers such as, but not limited to, Thulmium or 355 nm. According tosome embodiments, a second laser may be used in conjunction with thelaser source producing the disclosed laser radiation in order tofacilitate coagulation. According to some embodiments laser cutting ofsub-mucosal plexus can be accompanied with energy induced damage ofneural elements in the tunica muscularis with mechanical cutting toavoid wall perforation. According to some embodiments, mechanicalcutting depth is determined by imaging. According to some embodiments,the controlling and imaging cutting depth is done in real time.

IV. Laser Absorption in Target Area Tissue and Tissue Outside of TargetArea

Reference is now made to FIG. 4, illustrating, according to someembodiments, blocking of neural activity in the duodenal wall by use oflaser radiation which can be absorbed in tissue outside the target area.FIG. 4 depicts a longitudinal cross section through part of duodenum(400) and catheter (416) which is introduced into the lumen of duodenum(400). The duodenum wall of duodenum (400) comprises the mucosal layer(402A, 402B), the submucosal layer (404A, 404B) which comprisessubmucosal plexus (406A and 406B, respectively), circular muscle (408A,408B), myentric plexus (410A, 410B), longitudinal muscle (412A, 412B)and mesenteric layer (414A, 414B).

Catheter (416) comprises laser element (418) and optic fiber (420) whichis partially comprised in laser element (418). According to someembodiments, laser element (418) is rotatable. Optic fiber (420) emitslaser radiation (422A, 422B) which is collimated by lens (440) andmanipulated by rotatable beam splitter (424) such that focused laserradiation (430) is focused through lens (442) at target area (432) inthe duodenal wall. Target area (432) comprises part of the sensoryneurons of submucosal plexus (406A). Laser radiation (426A, 426B) whichis back reflected and/or scattered is directed at imaging element (428)through lens (444). Imaging element (428) may be a camera or any imagingelement known in the art. According to some embodiments, lens (440) maybe used to generate the desired focus at the target area, obviating theneed for lens (442).

According to some embodiments, laser element (418) further comprises atleast one focusing element on a translator to align focal point, suchas, but not limited to, at least one lens (442), configured to focuslaser radiation (430) at target area (432). According to someembodiments laser element (418) may be used in the lumen of the duodenumor other lumens to create a series of impacts. According to someembodiments, lens (442) is a cylindrical lens which creates a line spotperpendicular to the lumen axis and is optionally rotated in steps inorder to create a circular impact in a cross-sectional plan of theduodenum perpendicular to the lumen axis.

According to some embodiments the target is other layers such asmulscularis or periphery of duodenum.

According to some embodiments, the energy level of laser radiation (430)is the highest at target area (432) on which it is focused. According toa non-limiting example, a spot 100 micron in diameter of a 1 Watt a CWlaser at 808 nm is obtained at the target to elevate the temperature bya few seconds to tens of seconds of illumination of the target area toinduce damage. According to some embodiments, laser radiation (430) isabsorbed in areas (434) and (436) surrounding target area (432) whereinthe temperature elevation induced is maintained below that which inducesdamage within the illumination period. According to some embodiments,the energy level provided to duodenal tissue by laser radiation (430) ishigher in target area (432) than in areas (434) and (436). According tosome embodiments, the damage induced by laser radiation (430) is higherin target area (432) than in areas (434) and (436). According to someembodiments, the thermal damage induced by laser radiation (430) ishigher in target area (432) than in areas (434) and (436). According tosome embodiments, the temperature elevation induced by laser radiation(430) is higher in target area (432) than in areas (434) and (436).According to some embodiments, the temperature elevation induced bylaser radiation (430) is higher in target area (432) than in areas (434)and (436) such that thermal damage is induced only in target area (432)and not in areas (434) and (436). According to some embodiments, theablation induced by laser radiation (430) is higher in target area (432)than in areas (434) and (436). According to some embodiments, the energytransferred to duodenal tissue by laser radiation (430) is higher intarget area (432) than in areas (434) and (436) such that it is highenough to induce ablation in target area (432) and not in areas (434)and (436). According to some embodiments, the affect induced by laserradiation (430) is higher in target area (432) than in areas (434) and(436), so as to cause a physical effect in the target area (432), butnot in areas (434) and (436).

According to some embodiments, the laser radiation is configured tocause damage to at least part of the sensory nerves within the targetarea while maintaining functional activity of tissue surrounding thesensory nerves. According to some embodiments, the laser radiation isconfigured to cause damage to at least part of the sensory nerves withinthe target area while maintaining functional activity of tissuesurrounding the sensory nerves within the target area. According to someembodiments, the laser radiation is configured to cause damage to atleast part of the nerves within the target area while maintainingfunctional activity of tissue surrounding the nerves within the targetarea. According to some embodiments, the laser radiation is configuredto cause damage to at least part of the sensory nerves within the targetarea while maintaining functional activity of tissue surrounding thetarget area. According to some embodiments, the damage is acutesub-ablative damage. According to some embodiments, inducing acutesub-ablative damage to nerves leads to a series of biochemical stepsculminating in neural cell death. According to some embodiments,efferent neurons are able to recover from damage induced according tothe present disclosure. According to some embodiments, efferent neuronsare able to recover from damage induced according to the presentdisclosure such that they maintain their functional activity.

According to some embodiments, the damage to the neurons is selectedfrom the group consisting of: thermal damage, ablation, mechanicaldamage and a combination thereof. Each possibility represents a separateembodiment of the present disclosure. According to some embodiments, onetype of damage to the neurons is denervation. According to someembodiments, the damage significantly reduces or completely abrogatesneural activity of sensory neurons within the target area. Eachpossibility represents a separate embodiment of the present disclosure.According to some embodiments, the damage results in cutting and/orremoving of at least part of the sensory neurons in the target area.Each possibility represents a separate embodiment of the presentdisclosure. According to some embodiments, the damage preventspropagation of neural signal within neurons and/or synapses at thetarget area. Each possibility represents a separate embodiment of thepresent disclosure.

V. Damage to Target Area

According to some embodiments, damage to sensory neurons in at least onetarget area within an organ of a subject, such as a subject's duodenumand/or within or in contact with at least part of a duodenal wallresults in blocking at least part of the signals generated in the targetarea such as but not limited to those induced by food passage throughthe duodenum. According to some embodiments, the signals induced by foodpassage through the duodenum are signals induced by chemo-receptorsand/or mechano-sensors within the duodenal wall. Each possibilityrepresents a separate embodiment of the present disclosure. According tosome embodiments, damage to sensory neurons in at least one target areawithin or in contact with at least part of a duodenal wall results inmodulation of motility in at least part of the gastrointestinal (GI)tract. According to some embodiments, modulation of motility refers toat least one of modulation of gastric accommodation and relaxationtriggered by meal passing through the duodenum and/or stomach. Eachpossibility represents a separate embodiment of the present disclosure.According to certain embodiments, the present disclosure provides amethod for blocking at least part of sensory neurons activated bypassage of food through the jejunum.

According to some embodiments, the damage is achieved by a single burstof the laser radiation towards the target area. According to someembodiments, the damage is achieved by a plurality of bursts of thelaser radiation towards the target area. As used herein, the term“plurality” refers to at least two. According to some embodiments, theplurality of bursts of laser radiation are provided uniformly in time.According to some embodiments, the plurality of bursts of laserradiation are provided with uniform intensity. According to someembodiments, the plurality of bursts of laser radiation are provided invarying amounts of time. According to some embodiments, the plurality ofbursts of laser radiation are provided with varying intensity. Accordingto some embodiments, a beam compressor or a pulse compressor is used inconjunction with the elements used to rotate, manipulate or scan thebeam. According to some embodiments, focusing the laser radiation on thetarget area induces damage in a form selected from the group consistingof: a straight line, a curved line, a circle, a circle sector, a dot, aspot and a combination thereof. Each possibility represents a separateembodiment of the present disclosure. In certain embodiments, damage toa target area, such as, but not limited to, the submucosal plexus isinduced by focusing the laser radiation to a plurality of locationsalong the target area. Without wishing to be bound by any theory ormechanism, focusing the laser radiation to a plurality of locationsalong a target area may facilitate impacting the target area whileminimizing side effects and/or damage to surrounding tissue.

According to some embodiments, the laser radiation is configured tocause damage to neurons within the target area with causing no damage orminimal damage to tissue surrounding the neurons in the target area.Each possibility represents a separate embodiment of the presentdisclosure. According to some embodiments, the laser radiation isconfigured to cause damage to sensory neurons within the target areawith causing no damage or minimal damage to tissue surrounding thesensory neurons in the target area. Each possibility represents aseparate embodiment of the present disclosure.

According to some embodiments, nerves are more sensitive to thermaldamage than tissues such as, but not limited to, vasculature, muscle andlymphatic vessels. According to some embodiments, exposing nerves to atemperature of about 45-75° C. induces thermal damage to the nerves.According to some embodiments, exposing nerves to a temperature of about45-55° C., 55-75° C. or 60-75° C. induces thermal damage to the nervesby a short exposure of less than a minute typically. Each possibilityrepresents a separate embodiment of the present disclosure.

According to some embodiments, thermal damage to nerves significantlyreduces or abrogates neural activity in the nerves. According to someembodiments, exposure of nerves to heat of at least about 60° C.,typically at least about 65° C. degrees for about 30-60 seconds,typically about 20-50, 10-40 or 5-30 seconds is sufficient to inducethermal damage in the nerves. Each possibility represents a separateembodiment of the present disclosure. It is to be noted that inducingthermal heat in nerves using high temperatures may be done in seconds,while inducing thermal heat using lower temperature may require severalminutes. The time required to induce temperature elevation at the targetarea may be less than a minute when temperature such as 65° C. arereached, may be above 10 minutes at lower temperatures or may be secondsat higher temperatures. Without wishing to be bound by any theory ormechanism, exposing a target area comprising neurons to laser energy mayinduce thermal damage in nerves prior to damaging other tissues withinthe target area. Accordingly, focusing laser radiation to a target areamay be used to induce thermal damage to neurons within the target areawithout inducing damage to other tissues within the target area.

VI. Methods and Systems for Treating a Medical Condition

According to some embodiments, the present disclosure provides a methodfor treating a medical condition selected from the group consisting of:obesity, type 2 diabetes mellitus, insulin resistance and a combinationthereof in a subject, the method comprising:

-   -   introducing at least one laser element into a lumen of the        subject's duodenum;    -   actuating the laser element to emit laser radiation;    -   focusing the laser radiation to a target area within or in        contact with at least part of a duodenal wall, wherein the        target area comprises sensory nerves, such that the radiation is        configured to cause damage to at least part of the sensory        nerves while maintaining functional activity of tissue        surrounding the sensory nerves.

According to some embodiments, the disclosed method of treatment isconfigured to modulate selective and local signals induced by foodand/or physiological functions associated with food ingestion. Accordingto some embodiments, interventions, such as damage induced by laserradiation, may be performed at several locations along the duodenal walland/or in contact with the duodenal wall in order to target pathways andsensors spread across the various layers of the duodenal wall and toaffect various mechanisms involved in conditions such as, but notlimited to, type 2 diabetes and obesity. According to some embodiments,one or more locations along the duodenum can be impacted according tothe disclosed methods. According to some embodiments, locations proximalto the duodenum such as the distal gastric region and/or pylorus of thestomach may be impacted. According to some embodiments, locations distalto the duodenum such as the duodenal-jejunal junction and the jejunummay be impacted. According to some embodiments, the term “impacted”refers to an area on which laser radiation is focused. According to someembodiments, the term “impacted” refers to an area comprising sensoryneurons on which laser radiation is focused.

According to another aspect, the present disclosure provides anendoluminal duodenal catheter for blocking at least part of the neuralactivity in a duodenum of a subject in need thereof, the cathetercomprising:

-   -   a laser element configured to emit laser radiation; and    -   a rotatable optical element configured to direct the laser        radiation to one or more target areas within or in contact with        at least part of a duodenal wall, wherein the target area        comprises sensory nerves, such that the radiation is configured        to cause damage to sensory nerves while maintaining functional        activity of tissue surrounding the sensory nerves.

According to some embodiments, at least a part of a laser element isconfigured to emit laser radiation.

According to some embodiments, the catheter comprises a laser elementconfigured to emit laser radiation. According to some embodiments, thecatheter further comprises a laser source functionally connected to thelaser element. According to some embodiments, the laser elementcomprises at least one optic fiber configured to emit laser radiation.According to some embodiments, the laser element comprises at least onefocusing element configured to focus the laser radiation to the targetarea. According to some embodiments, the catheter further comprises atleast one mechanical element configured to induce damage, such as, butnot limited to, a blade, a rotating knife and a combination thereof.

VII. Pressure-Inducing Element

According to some embodiments, the endoluminal duodenal catheter furthercomprises at least one pressure-inducing element. According to otherembodiments, the disclosed system comprises at least onepressure-inducing element. According to some embodiments, the at leastone pressure-inducing element is configured to exert pressure on atleast part of the duodenal wall. According to some embodiments, the atleast one pressure-inducing element is configured to exert pressure onat least part of the duodenal wall and stretch it benefiting from itscompliant structure. According to some embodiments, the at least onepressure-inducing element is configured to exert pressure on at leastpart of the duodenal wall thus controlling the distance between thetarget area and optical axis and determining the optical path length.According to some embodiments, the at least one pressure-inducingelement is configured to exert pressure on at least part of the duodenalwall thus changing thickness of the duodenal wall or part thereof.According to some embodiments, changing thickness of the duodenal wallor part thereof enables to shorten the optical path of the laserradiation and/or bring the target area to a desired thickness. Eachpossibility represents a separate embodiment of the present disclosure.According to some embodiments, the at least one pressure-inducingelement is configured to hold the laser element in place and/or to fixthe laser element in a predetermined location. According to someembodiments, the at least one pressure-inducing element is in the formof a balloon. Without wishing to be bound by any theory or mechanism,exerting pressure on the duodenal wall using at least onepressure-inducing element may serve to overcome the inter and intrapatient variability in the thickness and/or shape of the duodenal walllayers that may induce alteration in laser absorption and/or heattransfer interaction at the targeted layer.

According to some embodiments, the at least one pressure-inducingelement is functionally connected to the catheter and/or laser element.Each possibility represents a separate embodiment of the presentdisclosure. According to some embodiments, the at least onepressure-inducing element surrounds and/or connected to at least part ofthe catheter/and or laser element. Each possibility represents aseparate embodiment of the present disclosure. According to someembodiments, the at least one pressure-inducing element comprises atleast part of the laser element. According to a non-limiting example,the pressure-inducing element is a balloon comprising at least part ofthe laser element.

According to some embodiments, the pressure-inducing element isconstructed from polymers that have high transparency configured toenable passage of laser radiation through the pressure-inducing elementand withstand high-power laser radiation. According to some embodiments,the pressure-inducing element is made of at least one polyamide.

Reference is now made to FIGS. 5A and 5B illustrating, according to someembodiments, a catheter comprising pressure inducing elements in theform of balloons.

FIG. 5A depicts a longitudinal cross section through part of duodenum(500A) and catheter (516) which is introduced into the lumen of duodenum(500A). The duodenal wall of duodenum (500A) comprises the mucosal layer(502A, 502B), the submucosal layer (504A, 504B) which comprisessubmucosal plexus (506A and 506B, respectively), circular muscle (508A,508B), myentric plexus (510A, 510B), longitudinal muscle (512A, 512B)and mesenteric layer (514A, 514B). FIG. 5B depicts the longitudinalcross section depicted in FIG. 5A after deflated pressure-inducingelements (528, 534, 536, and 542) have been inflated topressure-inducing elements (528′, 534′, 536′, and 542′) and inducedpressure on the duodenal wall of duodenum (500B). Accordingly, FIG. 5Bdepicts a longitudinal cross section through part of duodenum (500B) andcatheter (516′) which is introduced into the lumen of duodenum (500B).The duodenal wall of duodenum (500B) comprises the mucosal layer (502A′,502B′), the submucosal layer (504A′, 504B′) which comprises submucosalplexus (506A′ and 506B′, respectively), circular muscle (SOSA′, 508B′),myentric plexus (510A′, 510B′), longitudinal muscle (512A′, 512B′) andmesenteric layer (514A′, 514B′).

Catheter (516) comprises laser element (518) and optic fiber (520) whichis partially comprised in laser element (518). Laser element (518) isnot-actuated such laser radiation is not emitted. Optic fiber (520) isconfigured to emit laser radiation directed at rotatable prism (524)such that focused laser radiation is directed at a target area in theduodenal wall. Catheter (516) and laser element (518) comprisepressure-inducing elements (528, 534, 536, and 542) in the form ofballoons which are deflated and do not induce pressure on the duodenalwall of duodenum (500A). According to some embodiments, Laser element(518) is configured to be actuated only once pressure-inducing elements(528, 534, 536, and 542) have been inflated and induced pressure on theduodenal wall. According to some embodiments, Laser element (518) isconfigured to be actuated only once pressure-inducing elements (528,534, 536, and 542) have inflated and induced pressure on the duodenalwall such that pre-determined optical path length distance (550) isachieved. According to certain embodiments, a controller is used tocontrol actuation of deflated pressure-inducing elements (528, 534, 536,and 542).

Following inflation of deflated pressure-inducing elements (528, 534,536, and 542) to pressure-inducing elements (528′, 534′, 536′, and542′), pressure was induced on duodenal wall of duodenum (500B) suchthat the thickness of duodenal wall layers is reduced. According to someembodiments, deflated pressure-inducing elements (528, 534, 536, and542) are inflated to pressure-inducing elements (528′, 534′, 536′, and542′) until pre-determined optical path length (550) is reached.According to some embodiments, submucosal layer (504A) and mucosal layer(502A) having thickness (X) turn into submucosal layer (504A′) andmucosal layer (502A′) having lower thickness (X′) following the pressureinduced by inflated pressure-inducing elements (528′, 534′, 536′, and542′). Concomitantly or following inflation of pressure-inducingelements (528′, 534′, 536′, and 542′), optic fiber (520′), comprised inlaser element (518′), emits laser radiation (522) which is rotated byrotatable prism (524′) such that laser radiation (526) is directed attarget area (544) comprising part of submucosal plexus (506A′).According to some embodiments, due to the pressure exerted on the wallof duodenum (500B) by inflated pressure-inducing elements (528′, 534′,536′, and 542′) at least layers (502A′) and (504A′) are thinner and thusthe optical path of laser (526) is shortened and less subject tovariability in shape of villi mucosal surface. According to someembodiments, catheter (516′) may be repositioned by deflating inflatedpressure-inducing elements (528′, 534′, 536′, and 542′), moving catheter(516′) and re-inflating the pressure-inducing elements at the desiredposition.

According to some embodiments laser element (518) is located inside atransparent balloon which enables passage of laser radiation such thatthere is no need for an opening in the balloon. According to someembodiments the laser element can move along the lumen axis inside theballoon with no need to move the balloon to generate impact in severalplaces along the lumen axis.

According to some embodiments the laser element is positioned in placeby a tripod. In some embodiments the tripod is used to stretch theduodenum to predetermine optical distance (550).

According to certain embodiments, the pressure-inducing elements areinflated via air or via an inert gas. According to certain embodiments,the pressure-inducing element is filled with liquid to facilitateacquisition of acoustic wave associated with the photo-acoustic effectfor purpose of optical alignment and/or on-line process monitoring. Incertain embodiments, at least one acoustic transducer is assembledwithin the catheter.

According to some embodiments, the present disclosure provides thedisclosed endoluminal duodenal catheter for use in blocking at leastpart of the neural activity in a duodenum of a subject in need thereof.According to some embodiments, the present disclosure provides thedisclosed endoluminal duodenal catheter for use in treatment of amedical condition selected from the group consisting of: obesity, type 2diabetes, insulin resistance and a combination thereof in a subject.

According to another aspect, the present disclosure provides a systemfor use in blocking at least part of the neural activity in at least oneneural region in a duodenum of a subject in need thereof, the systemcomprising:

-   -   an endoluminal duodenal catheter for blocking at least part of        the neural activity in a duodenum of a subject in need thereof,        the catheter comprising:        -   at least a part of a laser element configured to emit laser            radiation; and        -   a rotatable optical element configured to direct the laser            radiation to one or more target areas within or in contact            with at least part of a duodenal wall, wherein the target            area comprises sensory nerves, such that the radiation is            configured to cause damage to sensory nerves while            maintaining functional activity of tissue surrounding the            sensory nerves;    -   an imaging device configured to capture structural information        related to the duodenal wall or an area in contact with at least        part of a duodenal wall; and    -   a controller configured to determine said one or more target        area based on the structural information.

VIII. Optical Lens Systems and Beam-Splitting of Laser Element

According to some embodiments, the methods and systems use an opticalelement. According to some embodiments, the optical element is arotatable optical element. According to some embodiments, the rotatableoptical element is a wide-angle lens system. According to someembodiments, the rotatable optical element is a lens capable ofcorrecting f-theta distortion or f-sin(theta) distortion. According tosome embodiments, the rotatable optical element is a dove prism, areversion or “K” prism, a Delta or Pechan prism, or any other associatedprism known in the art.

According to other embodiments, the rotatable optical element is adispersive prism, a reflective prism, a beam-splitting prism or adeflective prism. According to some embodiments, the prism is a low-lossdeflective prism. According to some embodiments, the dispersive prism isa triangular, a Pellin-Broca prism, an Abbe Prism or a compound pnsm.

According to other embodiments, the prism has a triangular ortrapezoidal shape. According to other embodiments, the form of the prismis made from glass (i.e., BK7 glass or fused silica) and is designed fora laser such as a diode laser, fiber laser or a nNd:YAG laser beam.

According to other embodiments, the prism is a Gian-Taylor prism or aGian-laser pnsm. According to other embodiments, the prism is anequilateral glass prism.

According to other embodiments, the prism is selected from a groupconsisting of anamorphic Prism Pairs, a high-powered laser-light rightangle prism, a hollow retroreflector, a laser-line right angle prism, aN-BK7 Corner Cube Retroflector or a UV Fused Silica Corner CubeRetroflector.

According to some embodiments, a prism compressor or a pulse compressoris used in conjunction with the prism.

According to some embodiments, the laser element may further comprise anactuator for rotating the rotatable optical element. The actuator may bea hydraulic, mechanical, or an electrical/electronic actuator; and, mayutilize pins, gears, magnets, or other type of elements, that caninitiate and control the rotation of the rotatable optical element.

According to some embodiments, the actuator uses a wire to initiate andcontrol the rotation of the rotatable optical element.

According to some embodiments, the laser element may comprise acontroller for actuating the optical rotator in accordance with an inputsignal from an input device. The controller may be processor and/ormicroprocessor based for precisely regulating the position of theactuator. The controller may contain circuitry necessary to interpretand execute instructions from an input device. As a result ofinterpreting and executing the instructions, the controller may outputcorresponding instructions and/or signals to initiate and regulate theactuator position.

According to some embodiments, the actuating of the rotatable opticalelement may be automatic, where the portion of a wide viewing field,and/or a region of interest within the wide view field, may beautomatically selected from standard viewing angles typically used,including, but not limited to, 0, 30, 45, 70, 90, 120, 180 degrees fromthe longitudinal axis of the catheter.

According to some embodiments, the rotatable optical element isconfigured to rotate and/or split the laser beam emitted by the laserelement. Each possibility represents a separate embodiment of thepresent disclosure. According to some embodiments, the rotatable opticalelement is configured to rotate the laser beam emitted by the laserelement. According to some embodiments, the rotatable optical element isconfigured to enable rotational movement of laser radiation emitted bythe laser element around the longitudinal axis of the duodenum.According to some embodiments, the rotatable optical element isconfigured to rotate concomitantly with movement of the laser elementalong the duodenum, such that the emitted laser radiation generates aspiral-like ablation pattern. According to some embodiments, the emittedlaser radiation generates a helical-like ablation pattern. According tosome embodiments, the emitted laser radiation generates a circular orcylindrical-like ablation pattern.

According to some embodiments, an optical is provided that may fold androtate emitted laser radiation or a laser beam.

According to some embodiments, the rotatable optical element isconfigured to enable splitting of laser radiation. According to someembodiments, the rotatable optical element is configured to enablesplitting of laser radiation such that part of the laser radiation isdirected at a target area and part of the laser radiation is directed atan imaging element, such as, but not limited to, a camera. According tosome embodiments, the camera includes a controller, the controller beingable to process data provided by part of the laser radiation. Accordingto some embodiments, the imaging element is located in the distal regionof the catheter.

According to some embodiments, the laser element is rotatable. Accordingto some embodiments, the laser element itself is a rotatable opticalelement. According to some embodiments, the laser element is rotatablesuch that the laser radiation emitted by the laser element is configuredto move in at least part of a rotational trajectory around thelongitudinal axis of the duodenum. Without wishing to be bound by theoryor mechanism, using a laser element comprising a rotatable opticalelement, such as a rotatable prism, enables to ablate a ring-like targetarea along the duodenal wall.

According to some embodiments, the laser element further comprises anactuator for rotating the laser element itself. The actuator may be ahydraulic, mechanical, or an electrical/electronic actuator; and, mayutilize pins, gears, magnets, or other type of elements, that caninitiate and control the rotation of the rotatable optical element.

According to some embodiments, the laser element is functionallyconnected to a controller. According to some embodiments, the controlleris configured to actuate the laser element to emit laser radiation.According to some embodiments, the controller is configured to startand/or stop and/or direct the rotation of the rotatable optical element.Each possibility represents a separate embodiment of the presentdisclosure. According to some embodiments, the controller is configuredto determine the target area to which the laser radiation is directed.According to some embodiments, the controller is able to select standardangles of rotation including, but not limited to, 0, 30, 45, 70, or 90degrees from the longitudinal axis of the catheter.

According to some embodiments, the laser element comprises at least oneaperture configured to enable directed emission of laser radiation.According to some embodiments, the laser element comprises at least onefocusing element, configured to focus the laser radiation. According tosome embodiments, the laser element comprises at least one focusingelement, configured to focus the laser radiation on a target area.According to some embodiments, the focusing element is at least onelens. According to some embodiments, the lens may be a correction lens.According to some embodiments, the focusing element allows the laserradiation to be tapered or allows the laser radiation to be channeledthrough a narrow element. According to some embodiments, the lenscorrects aberration. The aberration may be spherical aberration, axialchromatic aberration and any other types of known aberrations in theart.

According to some embodiments, the lens does not contribute todistortion, lateral chromatic aberration, astigmatism or fieldcurvature.

According to some embodiments, the lens is capable of removing f-thetadistortion. An f-theta optical lens uniformly separates the light raysincident to a wide angle lens by a distance proportional to f-theta,where f is the focal distance of the lens system and theta is the angleof incidence of the image rays relative to optical axis. The f-thetaoptical lens provides a uniform distribution of the image field relativeto the optical axis such that equivalent solid angles in the object willbe imaged onto equivalently sized regions of the 1 magmg area.

According to some embodiments, the lens is capable of removingf-sin(theta) distortion. In an f-sin(theta) optical system the radialheight of an image relative to the image location of the optical axis isproportional to the sine of the corresponding object angle from which itoriginated. An f-sin(theta) optical system provides a uniform f-numberacross the image plane, and therefore uniform illumination andpotentially uniform MTF. An f-sin(theta) optical system allows for equalsolid angles in object space to be imaged onto equal areas of the imageplane.

If the optical system does not correct the variation in informationdensity attributable to the wide angle lens system, then it may benecessary to provide circuitry that can correct any distortion or uneveninformation density that can be present in the image signal or theregion of interest signal. However, by utilizing an f-theta opticalsystem, the need to incorporate corrective circuitry and thecomplexities associated with such manipulation can be avoided.

According to some embodiments, the system may further comprise anillumination system. The illumination system may provide light into thelumen of a subject's duodenum. The illumination system may be made ofone or more light emitting diodes (LEDs). The illumination system mayfurther include other known methods for providing light into the lumenof a subject's duodenum.

According to some embodiments, the system may further comprise adisplay, the display able to display a view the lumen of a subject'sduodenum.

Reference is now made to FIG. 6, illustrating, according to someembodiments, blocking or modulation of neural activity in the duodenalwall by use of laser radiation which is not configured to be stronglyabsorbed in the lumen wall. FIG. 6 depicts a longitudinal cross sectionthrough part of duodenum and catheter (604) which is introduced into thelumen of duodenum.

Catheter (604) comprises laser element having optic fiber (602) which ispartially comprised in the laser element. Optic fiber (602) emits laserradiation (620A, 620B) which passes through a focusing element, such asbut not limited to, at least one lens element (606) and is rotated byrotatable beam splitter (624) such that focused laser radiation (630A,630B) is directed at a target area. According to some embodiments, asecond lens element (640) also is provided to focus laser radiation attarget area. According to some embodiments, the at least one focusingelement is able to focus the laser radiation at angles, including, butnot limited to, 0, 30, 45, 70, 90 or 120 degrees from the longitudinalaxis on the catheter (604).

The at least one lens element (606) may include aspherical, aspehericcylindrical or correction lens or other types of lenses that are able tofocus the laser and reduce aberration. To assist in focusing the laserat the pre determined target, physical means that are provided to selectan appropriate layer of focus are also shown.

As shown in FIG. 6, physical means include blocking elements (612, 614,608 and 610) that help control and/or focus the laser by producing acontrolled aperture. According to some embodiments, elements (612, 614)are used to ensure that the laser beam generates a the required spot atthe pre-determined layer. According to some embodiments, elements (608,610) are used to form an aperture to assure the image acquired is fromthe layer of interesting and to block scattered light from other layers,in analogy to the principles of confocal microscopy.

Furthermore, an imaging element (628) is shown, such that laserradiation (635A, 635B) is back reflected, scattered or emanating from anadjunct source and is collected by imaging element (628). Imagingelement (628) may be any suitable element for capturing informationthrough lens (642) such as, but not limited to a single detector,detector arrays, camera or detector, such as a CCD and CMOS chips.According to some embodiments, imaging element (628) is configured tocapture information about the structure of the duodenum and/orsurrounding tissue and/or monitor the process on-line by monitoringchanges in the optical characteristics of tissue following interactionof tissue with the laser beam. Each possibility represents a separateembodiment of the present disclosure.

FIG. 6 further provides that rotatable beam splitter (624) is able tofold the laser, thereby creating automatically or semi-automatically acircular modulation of/impact on the tissue around the duodenal axis andoptionally containing an accessory for imaging of the focus to enableselection of the appropriate layer. In certain embodiments rotatablebeam splitter (624) is able to reflect the beam to the tissue through alens and control the angle of deflection while having partialtransmittance to enable light that is back reflected, scattered orfluorescence emitted from the tissue to pass through the beam splitter.In case of fluorescence, beam splitter (624) may be made from a dicrohicmirror known in the art so that the laser beam is effectively deflectedwhile in other wavelengths the light energy passes through filtered bythe aperture formed by element (610,608) and transferred using lens(642) to imaging element (628) FIG. 7 illustrates an alternativeembodiment to FIG. 6 that uses a laser that is partially absorbed by thetissue, but the beam is focused to the targeted layer to cause its mainimpact there while minimizing its collateral impact on layers above andbelow the targeted layer. In the figure the focus is in the sub mucosallayer.

Reference is now made to FIG. 7, illustrating, according to someembodiments, blocking of neural activity in the duodenal wall by use oflaser radiation which can be partially absorbed in tissue outside thetarget area. FIG. 7 depicts a longitudinal cross section through part ofduodenum (700) and catheter (704) which is introduced into the lumen ofduodenum (700). The duodenum wall of duodenum (700) comprises themucosal layer (702A, 702B), the submucosal layer (704A, 704B) whichcomprises submucosal plexus (706A and 706B, respectively), circularmuscle (708A, 708B), myentric plexus (710A, 710B), longitudinal muscle(712A, 712B) and mesenteric layer (714A, 714B).

Catheter (704) comprises laser element and optic fiber (702) which ispartially comprised in laser element. Optic fiber (702) emits laserradiation (726A, 726B) which is split by beam splitter (724) and passesthrough focusing lens (706) such that focused laser radiation (730A,730B) is directed at target area (732) in the duodenal wall, whichcomprises part of the sensory neurons of submucosal plexus (4706A).According to some embodiments, since the laser element emits a largespot, focusing lens (706) is positioned before the beam rotator.According to certain embodiments, typical lenses with focal length of afew cm may be used in such a configuration to create a spot in the orderof 100 micron to less than 1 mm in diameter, wherein according to thelaser used single vs. multimode and spot required the lens is selected.

Beam splitter (724) with imaging lens (730) are used to collect backreflected, scattered, or fluorescence light from the tissue and directit at imaging element (728). Laser radiation, such as radiation (735A,735B) is directed at imaging element (728) through lens (730). Imagingelement (728) may be a camera or any imaging element known in the art.

According to some embodiments, a catheter is placed in the center of thelumen, that includes an optical head that can fold and rotate the beam,with stand offs that can hold the catheter in place such as by use of aballoon with appropriate pressure to determine the relative positionallowing repositioning by a physician if required by deflating andre-inflating or slipping over the lumen. The head may include means forautomatic linear movement across the duodenum. The balloon can beconstructed from polymers that have high transparency for the laser beamand can withstand a relative high power. An example of a material thatmay be use are polyamides.

Reference is now made to FIG. 8 illustrating, according to someembodiments, a catheter comprising pressure inducing elements in theform of balloons.

FIG. 8 depicts the longitudinal cross section depicted in after deflatedpressure-inducing elements have been inflated to pressure-inducingelements (828, 834, 836, and 842) and induced pressure on the duodenalwall of duodenum (800). Accordingly, FIG. 8 depicts a longitudinal crosssection through part of duodenum (800) and catheter (816) which isintroduced into the lumen of duodenum (800). The duodenal wall ofduodenum (800) comprises the mucosal layer (802A, 802B), the submucosallayer (804A, 804B) which comprises submucosal plexus (806A and 806B,respectively), circular muscle (SOSA, 808B), myentric plexus (810A,810B), longitudinal muscle (812A8, 812B) and mesenteric layer (814A,814B).

Catheter (816) comprises laser element and optic fiber (820) which ispartially comprised in laser element. Optic fiber (820) is configured toemit laser radiation directed at rotatable prism (824) such that focusedlaser radiation is directed at a target area in the duodenal wall.Catheter (816) and laser element comprise pressure-inducing elements(828, 834, 836, and 842) in the form of balloons. According to someembodiments, Laser element (818) is configured to be actuated only oncepressure-inducing elements (828,834, 836, and 842) have been inflatedand induced pressure on the duodenal wall. According to certainembodiments, a controller is used to control actuation ofpressure-inducing elements (828, 834, 836, and 842).

Following inflation of deflated pressure-inducing elements topressure-inducing elements (828, 834, 836, and 842), pressure wasinduced on duodenal wall of duodenum (800) such that the lumen isstretched to increase its effective diameter by utilizing its certaincompliance capability such that pre-set optical path distance (850)between the target area and the optical axis of catheter (816) isachieved. According to certain embodiments the thickness of duodenalwall layers is reduced using pressure-inducing elements (828, 834, 836,and 842). Concomitantly or following inflation of pressure-inducingelements (828, 834, 836, and 842), optic fiber (820), comprised in laserelement (818) emits laser radiation (820A, 820B) which is rotated byrotatable prism (824) such that laser radiation (830A, 830B) is directedat target area (844) comprising part of submucosal plexus (806A).According to some embodiments, due to the pressure exerted on the wallof duodenum (800) by inflated pressure-inducing elements (828, 834, 836,and 842) at least layers (802A) and (804A) are thinner and thus theoptical path of laser (830A, 830B) is shortened. In certain embodimentsthe laser (830A, 830B) is focused at the required layer (such assubmucosa 804A) by setting the predetermined optical distance (850)which guarantees the laser focal point is at the required layerregardless of inter and intra patient variability in lumen diameter andvilli shape. According to other embodiments, the focusing lens (840) canbe on variable translator to enable focusing on the required targetbased on imaging information. According to some embodiments, catheter(816) may be repositioned by deflating inflated pressure-inducingelements, moving catheter (816) and re-inflating the pressure-inducingelements at the desired position.

According to some embodiments pressure-inducing elements (828, 834, 836,and 842) are at least partially filled with liquid and include one ormore acoustic transducers (855) to collect acoustic waves for thepurpose of acousticoptic microscopy.

According to some embodiments, optic fiber (820) emits laser radiation(820A, 820B) which passes through a focusing element, such as but notlimited to, at least one lens element (840) and is rotated by rotatableprism (824) such that focused laser radiation (830A, 830B) is directedat a target area. The at least one lens element (840) may includespherical or cylindrical lenses to produce round spots or lines and caninclude aspheric or cylindrical aspheric correction lens or other typesof lenses that are able to focus the laser and reduce aberration. Toassist in focusing the laser, physical means are provided to select anappropriate layer of focus is also shown.

In all of FIGS. 6-8, the rotatable optical elements are capable ofrotating the beam and in some cases also enable light to be collectedfor imaging purposes. The same or other elements can be used to deflectthe beam in angles different than 90 degrees or to scan a spot andgenerate a line parallel to the lumen axis. According to someembodiments, focusing elements such as lenses are used, which canfurther facilitate laser beam manipulation to direct the laser beam(s)on the target area and on imaging elements.

IX. Imaging Systems

According to some embodiments, the imaging device is configured tocapture structural information related to the duodenal wall or an areain contact with at least part of a duodenal wall, to determine thatlight is focused at the required layer (i.e, submucusal, muscularis,peripheral at the interface with ganglion or vagal nerves or in VANinterface) and/or to monitor interaction with tissue on-line for processcontrol. Each possibility represents a separate embodiment of thepresent disclosure. According to some embodiments, the imaging device isconfigured to capture structural information related to the target area.According to some embodiments, the imaging device is configured toenable location of the target area based on structural informationrelated to the duodenal wall or an area in contact with at least part ofa duodenal wall. Each possibility represents a separate embodiment ofthe present disclosure. According to some embodiments, the imagingdevice is configured to enable visualization of the target area based onstructural information related to the duodenal wall or an area incontact with at least part of a duodenal wall. Each possibilityrepresents a separate embodiment of the present disclosure. According tosome embodiments, the imaging device includes a camera or video deviceable to receive signals, such that the structural information related tothe duodenal wall or an area in contact with at least part of a duodenalwall is able to be collected. According to some embodiments the imagingdevice provides information about the temperature at the target.According to some embodiments, the imaging device allows a user to focusthe laser, such that that user has visual guidance within the duodenumof a subject, when using the catheter. According to some embodiments,visual guidance can be done automatically based on pre-determinedalgorithms.

According to some embodiments, the imaging device is configured tocapture structural information related to thickness of at least onelayer in the duodenal wall. According to some embodiments, the imagingdevice is configured to enable localization of the target area and/or alayer in the duodenal wall comprising the target area. Each possibilityrepresents a separate embodiment of the present disclosure. According tosome embodiments, the structural information relates to at least one of:thickness of duodenal wall layers, location of neurons, location ofsensory neurons, location of blood vessels, blood flow through bloodvessels, temperature, changes in optical characteristics of the targetand lumen wall and a combination thereof. Each possibility represents aseparate embodiment of the present disclosure.

According to some embodiments, the imaging device is an endoscope.According to some embodiments, the imaging device is an endoscopeconfigured to be introduced into the lumen of the duodenum. According tosome embodiments, the imaging device is an ultrasound endoscopeconfigured to be introduced into the lumen of the duodenum and provideinformation about wall structure and thickness. According to someembodiments, the catheter comprises the imaging device. According tosome embodiments, the imaging device is a camera video device, singlechip or array detectors.

According to some embodiments, the imaging captured by the imagingdevice is optical imaging. According to some embodiments, imaging isthermal imaging. According to some embodiments, imaging is ultrasonicimaging. According to some embodiments, imaging is Infra-Red and/or NearInfra-Red imaging. Each possibility represents a separate embodiment ofthe present disclosure. According to some embodiments, imaging isOptical Coherence Tomography (OCT) based imaging. According to someembodiments, imaging is any combination of the above imaging modalities.According to a non-limiting example, the imaging device is configured touse ultrasound and/or NIR imaging and/or OCT imaging in order to capturestructural information relating to target areas comprising differentlayers of duodenum wall and sensory neurons that interface with theduodenal wall, such as, but not limited to, ganglions and/or vagalnerves. Each possibility represents a separate embodiment of the presentdisclosure. According to some embodiments, the imaging device isconfigured to locate the target area. According to some embodiments, theimaging device is configured to locate the target area based on bloodvessels residing near the target area using modalities such as, but notlimited to, ultrasonic energy, NIR imaging and a combination thereof.Each possibility represents a separate embodiment of the presentdisclosure. According to some embodiments, the imaging device isconfigured to locate the target area based on detecting blood vesselsand/or blood flow at vessels that are adjacent to sensory nerves ofinterest in the target area. Orientation of the imaging device and/orcatheter may be induced by manual rotation across the lumen and/or bysemiautomatic or automatic means. Each possibility represents a separateembodiment of the present disclosure.

According to some embodiments, the target area may be identifiedanatomically based on known landmarks, using imaging device, such as,but not limited to, an endoscope configured for optic imaging. Incertain embodiments, the target area may be identified usmg an imagingdevice configured for Near-Infra-Red imaging and/or visible light 1magmg and/or OCT imaging and/or ultrasound imaging and/or photo-acousticmicroscopy. Each possibility represents a separate embodiment of thepresent disclosure.

According to some embodiments, the target area may be identified throughmagnetic resonance imaging (MRI), microwaves, external ultra-sound,X-rays or a combination thereof Each possibility represents a separateembodiment of the present disclosure.

According to some embodiments, the imaging device is configured tocapture structural information related to the duodenal wall or an areain contact with at least part of a duodenal wall and thus enabledetermining whether the catheter is in the desired location within theduodenum and/or if damage has been caused at the target area. Eachpossibility represents a separate embodiment of the present disclosure.

According to some embodiments, the disclosed method further comprisesvarious types of imaging. According to some embodiments, the disclosedmethod further comprises imaging to obtain structural information of theduodenum. According to some embodiments, imaging is used to select thetarget area. According to some embodiments, imaging is used to monitorthe changes and/or determine the impact induced by the laser radiationat the target area. According to some embodiments, imaging is performedprior to direction of the focused laser radiation to the target area inorder to determine the location of the target area. According to someembodiments, imaging is performed using an imaging device, such as, butnot limited to, an endoscope. According to some embodiments, the imagingdevice is configured to use more than one imaging modality, such as, butnot limited to, ultrasonic imaging, NIR imaging, confocal imaging andOCT imaging

According to some embodiments, the disclosed system comprises acontroller. According to some embodiments, the controller is aprocessor. According to some embodiments, the controller is functionallyconnected with at least one of the laser element and the imaging device.Each possibility represents a separate embodiment of the presentdisclosure. According to some embodiments, the controller is configuredto actuate the laser element to emit laser radiation. According to someembodiments, the controller is configured to receive input from theimaging device. According to some embodiments, the controller receivesinput from an input device. According to some embodiments, input devicesare a mouse, keypad and/or a touchpad. According to some embodiments,the input devices are controlled by voice commands. According to someembodiments, the controller is configured to determine the identityand/or location of the one or more target area based on input relatingto structural information received from the imaging device. According tosome embodiments, the controller is configured to induce focusing of thelaser radiation to the target area,

According to some embodiments, the controller is functionally connectedto the rotatable optic element. According to some embodiments, thecontroller is configured to actuate rotation and/or determine thedirection and/or speed of rotation of the rotatable optic element. Eachpossibility represents a separate embodiment of the present disclosure.According to some embodiments, the controller is configured to inducerotation of the rotatable optic element such that the laser radiationmoves in at least part of a circular trajectory around the longitudinalaxis of the duodenum. According to some embodiments, the controller isconfigured to induce rotation of the rotatable optic element such thatthe laser radiation may be directed towards a plurality of target areas.According to some embodiments the controller can be configured togenerate a circle of intervention for blocking the signals in one placein submucoasal and/or muscularis plexuses and then move the optical heada few millimeters to generate another circle of impact and so forth toblock signals at different positions across the duodenal wall. Incertain embodiments the distance of these circles is smaller at theproximal part of the duodenum and larger at more distal parts. In someexamples the distance of the circles is in the range of 2-200 mm in thebeginning and 10-50 mm in more distal parts.

According to some embodiments, an actuator is used to actuate and/ordetermine the direction and/or speed of rotation of the rotatable opticelement. In certain embodiments, the actuator is controlled by voicecommands.

According to some embodiments, the disclosed system comprises at leastone pressure-inducing element. According to some embodiments, thecontroller is configured to actuate the at least one pressure-inducingelement to induce pressure on the duodenal wall. According to someembodiments, the controller is configured to actuate the at least onepressure-inducing element to induce pressure on the duodenal wall suchthat the laser element is fixed in the right place in the lumen of theduodenum.

According to some embodiments, the controller is configured to actuatethe at least one pressure-inducing element to induce pressure on theduodenal wall such that at least one layer in the duodenum wall changesthickness level. According to some embodiments, the controller isconfigured to be able to determine the level of pressure exerted by theat least one pressure-inducing element. According to some embodiments,the controller is configured to modulate the level of pressure exertedby the at least one pressure-inducing element depending on the requiredoptical path required for the laser radiation to cause damage in thetarget area.

According to certain embodiments, damage to neurons within a target areain the duodenal wall or in contact with the duodenal wall may be inducedby at least one energy form selected from the group consisting of: laserradiation, electrical energy, microwave energy, ultrasound and acombination thereof. Each possibility represents a separate embodimentof the present disclosure. According to certain embodiments, electricalenergy may be used in place of laser energy.

FIG. 9 schematically illustrates an endoscope having a catheterassembled on the endoscope. FIG. 9 illustrates another embodimentwherein electrical energy is used instead of laser energy for theinteraction with the tissue, by means of contact of the apparatus withthe tissue. This can be achieved by the use of a catheter that assembleson an endoscope (as schematically illustrated) or in a stand-alonecatheter.

According to FIG. 9, endoscope (902) includes a catheter (904) assembledon the endoscope. In certain embodiments the catheter or part of thecatheter described in previous figures is assembled on an endoscope. Incertain embodiments illustrated in FIG. 9 electrical energy is used toinduce damage to neural elements by means known in the field ofelectrophysiology. In FIG. 9, electrical energy is shown passing throughapertures (906,912) in catheter (904), using wires (908) and (910) usedto transmit high voltage to induce damage.

According to some embodiments, electrical energy is produced via a wireor via an electrical circuit According to some embodiments, protocols ofIrreversible Electroporation (IRE) such as 1,500 V/cm; with pulselength, 70 μs or higher to induce permanent damage may be used.According to some embodiments, electrical energy is provided via acapacitor. According to some embodiments, electrical energy is providedvia a device that transmits electrical energy. According to someembodiments, electrical energy is provided via terminal or pole thattransmits electrical energy.

According to some embodiments, microwaves may be used in place of laserenergy.

According to some embodiments, damage to neurons within a target area inthe duodenal wall or in contact with the duodenal wall may be induced byuse of ultrasound energy According to some embodiments, the ultrasoundenergy is focused energy. Non-limiting example of applicabletechnologies known in the art include, but are not limited to,microfocused ultrasound, laser induced focused ultrasound (LGFU) orEnhancement of focused ultrasound with micro-bubbles. According to someembodiments, the ultrasound energy is non-focused energy. According tosome embodiments, the ultrasound energy is focused such that it isconfigured to target the duodenal wall or layers within the wall orlayers at the periphery of the wall or non-focused such that it isconfigured to target the interface of sensory nerved of the duodenumwith the ganglia and/or vagal nerves. Each possibility represents aseparate embodiment of the present disclosure.

X. Photodynamic Therapy (PDT)

According to another aspect, the present disclosure provides methods andsystems for selectively blocking at least part of the neural activity ina target area within at least part of an organ of a subject, such as asubject's duodenum and/or the duodenal wall or in contact with theduodenal wall by using photodynamic therapy (PDT) to cause damage toneurons, typically sensory neurons, within the target area whilemaintaining functional activity of tissue surrounding the neurons and/orsurrounding the target area. Each possibility represents a separateembodiment of the present disclosure.

According to some embodiments, conventional photodynamic therapy (PDT)is used. Conventional photodynamic therapy (PDT) is based on theaccumulation of a photosensitizer in a specific tissue to producephototoxicity with minimal damage to surrounding tissue (Dougherty etal. J Natl Cancer Inst 90:889-905, 1998). Traditionally, PDT is thoughtto be mediated by the generation of ROS, especially singlet oxygen, inthe presence of oxygen (Dougherty et al. J Natl Cancer Inst 90:889-905,1998).

In vivo investigation of PDT in experimental gastrointestinal neoplasmshas demonstrated important biological advantages. Full thicknessintestinal damage produced by PDT, unlike thermal damage, does notreduce the mechanical strength of the bowel wall or cause perforation,because the sub-mucosal collagen is preserved.

According to some embodiments, PDT comprises illuminating a tissuecomprising a photosensitizer material which had been administered to thesubject systemically or locally with a light source configured to emitlight which is configured to induce the photosensitizer to inducedamage. Each possibility represents a separate embodiment of the presentdisclosure. According to some embodiments, PDT induces damage to tissuecomprising a photosensitizer while inducing no damage or non-significantdamage to the surrounding tissue. Each possibility represents a separateembodiment of the present disclosure. According to some embodiments, thedamage is cytotoxic damage. According to some embodiments, thephotosensitizer is promoted to an excited state upon absorption light toinduce generation of reactive oxygen species, such as, but not limitedto, singlet oxygen, thus inducing cytotoxic damage. According to someembodiments, a light source configured to emit light which is configuredto induce a photosensitizer to induce damage is a laser source, such as,but not limited to diode lasers, He—Ne laser & argon laser.

According to some embodiments, a light source may include a lightemitting device, emitting light at a therapeutic window, such as but notlimited to: 600-900 nm wavelength. According to some embodiments, alight source may include a fluorescent bulb to induce damage. Accordingto some embodiments, a light source may include a Xenon lamp to inducedamage.

According to some embodiments, a photosensitizer is a materialconfigured to induce damage when exposed to visible light. According tosome embodiments, a photosensitizer 1s a phototoxic material. Accordingto some embodiments, the photosensitizer is selected from the groupconsisting of: methylene blue, toluidine blue, janus green B,protoporphyrin IX, hematoporphyrin, chlorin e6, chlorin p6,m-tetrahydroxyphenylchlorin, riboflavin, acridine orange, sulphonatedzinc, sulfonated aluminum, phthalocyanine derivatives, phosphonatedaluminum phthalocyanine, Pd-bacteriophephorbide, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-alpha, motexafin lutetium, azure-C,phenothiazine derivatives, aminolevulinic acid derivatives, porfimersodium, verteporfin azadipyrromethenes derivatives, porphyrinderivatives, and haematoporphyrin derivatives and a combination thereof.Each possibility represents a separate embodiment of the presentdisclosure. According to certain embodiments, the photosensitizercomprises nanoparticles. According to some embodiments, thenanoparticles are used as carries thus increasing the photosensitizers'aqueous solubility, bioavailability and stability. According tonon-limiting examples, the nanoparticles include, but are not limitedto: colloid gold, quantum dots, paramagnetic nanoparticles, silica-basednanoparticles, polymer-based nanoparticles and a combination thereof.Each possibility represents a separate embodiment of the presentinvention. According to some embodiments, the nano-particles areintroduced into the duodenal wall endoluminally.

According to some embodiments the photosensitizer comprises liposomes.According to some embodiments the liposomes are targeted liposomes.According to some embodiments the liposomes are administered to thesubject systemically or locally. According to some embodiments, theliposomes are targeted to the small intestine, typically to theduodenum. Each possibility represents a separate embodiment of thepresent disclosure. According to some embodiments, the liposomes aretargeted to neurons. According to some embodiments, the liposomes aretargeted to sensory neurons. According to certain embodiments theliposome are passively targeted liposomes, actively targeted liposomes,or a combination thereof. Each possibility represents a separateembodiment of the present disclosure. According to some embodiments,actively targeted liposomes are antibody-modified liposomes orligand-modified liposomes. Each possibility represents a separateembodiment of the present disclosure. According to certain embodimentsat least one photosensitizer encapsulated in liposomes is releasedduring or before the treated tissue is irradiated. Each possibilityrepresents a separate embodiment of the present invention. According tocertain embodiments the liposomes are thermo-sensitive liposomes,fusogenic liposomes, pH-sensitive liposomes, light-sensitive liposomesor a combination thereof. Each possibility represents a separateembodiment of the present disclosure. According to some embodiments, theliposomes are introduced into the duodenal wall endoluminally.

According to some embodiments, the disclosed methods compriseintroducing at least one photosensitizer to at least one layer of theduodenal wall and/or to an area in contact with the duodenal wall. Eachpossibility represents a separate embodiment of the present disclosure.

According to some embodiments, at least one photosensitizer isintroduced to at least one layer or the duodenal wall and/or to an areain contact with the duodenal wall. Each possibility represents aseparate embodiment of the present disclosure. According to someembodiments, at least one photosensitizer is introduced to or proximalto the submucosal layer and/or the tunica muscularis layer of theduodenal wall. Each possibility represents a separate embodiment of thepresent disclosure. According to some embodiments, the at least onephotosensitizer is introduced to at least one target area comprisingneurons. According to some embodiments, the at least one photosensitizeris introduced to at least one target area comprising sensory neurons.According to some embodiments, the at least one photosensitizer isintroduced by injection and/or micro-injection and/or micro infusion.Each possibility represents a separate embodiment of the presentdisclosure. Introduction of at least one photosensitizer to at least onelayer or the duodenal wall may enable to induce selective damage to theat least one duodenal layer following illumination of the layer withsuitable light. According to some embodiments, the disclosed methodsfurther comprise introduction of at least one photosensitizer to thetarget area. According to some embodiments, the disclosed methodsfurther comprise introduction of at least one photosensitizer conjugatedto an antibody or antigen binding fragment to the target area. Accordingto some embodiments, the disclosed methods further comprise introductionof at least one photosensitizer to the target area and irradiation ofthe target area with light which is configured to induce thephotosensitizer to induce damage. According to some embodiments, thephotosensitizer is conjugated to an antibody or an antigen bindingfragment. Each possibility represents a separate embodiment of thepresent disclosure.

According to some embodiments, the present disclosure provides methodsand systems for selectively blocking at least part of the neuralactivity in a target area within the duodenal wall or in contact withthe duodenal wall by using targeted photodynamic therapy orphotoimmuno-therapy (PIT) to cause selective damage to neurons withinthe target area, preferably sensory neurons, while maintainingfunctional activity of tissue surrounding the neurons and/or surroundingthe target area. Each possibility represents a separate embodiment ofthe present disclosure.

According to some embodiments, the present disclosure provides methodsand systems for selectively blocking at least part of the neuralactivity in a target area of at least part of an organ of a subject,such as a subject's duodenum and/or within the duodenal wall or incontact with the duodenal wall by using targeted photodynamic therapy orphotoimmuno-therapy (PIT) to cause selective damage to neurons withinthe target area, preferably sensory neurons, while maintainingfunctional activity of tissue surrounding the neurons and/or surroundingthe target area. Each possibility represents a separate embodiment ofthe present disclosure.

According to some embodiments, photoimmuno-therapy (PIT) relates tophotodynamic therapy further comprising coupling and/or connecting atleast one photosensitizer to an antibody or antigen-binding fragmentssuch as, but not limited to, Fab fragments, Fab′ fragments, F(ab′)₂fragments, single-chain Fv fragments (scFvs) or a combination thereof toyield a conjugate. Each possibility represents a separate embodiment ofthe present disclosure. According to some embodiments, the at least onephotosensitizer is coupled with and/or connected to an antibody orantigen-binding fragment. Each possibility represents a separateembodiment of the present disclosure.

According to some embodiments, antigen-binding fragments of antibodiesinclude, but are not limited to, Fab fragments, Fab′ fragments, F(ab′)2fragments, and single chain Fv fragments. According to some embodiments,a photosensitizer coupled, connected or conjugated to an antibody orantigen-binding fragment retains the photosensitizing effects of saidphotosensitizer and the binding properties of the antibody or antigenbinding fragment. Each possibility represents a separate embodiment ofthe present disclosure. According to some embodiments the at least onephotosensitizer is coupled with and/or connected to an antibody orantigen-binding fragment via at least one linker, such linkers are knownto those skilled in the art.

According to some embodiments, the antibody or antigen-binding fragmentbinds specifically to neurons. According to some embodiments, theantibody or antigen-binding fragment binds specifically to neuronsand/or nerve fibers and/or synapses. Each possibility represents aseparate embodiment of the present disclosure. According to someembodiments, the at least one photosensitizer is conjugated to anantibody or antigen binding fragment configured to specifically bindneuronal tissue by targeting neuronal elements suc as, but not limitedto: myelin basic protein, neurofilaments, choline acetyltransferase andProtein Gene Product 9.5 (PGP 9.5). Each possibility represents aseparate embodiment of the present disclosure.

According to some embodiments, the antibody or antigen-binding fragmentbinds specifically to sensory neurons rather than motor neurons.According to certain embodiments a photosensitizer-antibody conjugatecomprises an antibody or fragment thereof that targets sensory orafferent neural elements. According to non-limiting examples, theantibody or antigen binding fragment may be configured to bind antigenssuch as, but not limited to: Acid sensing ion channel 3 (ASIC3), Acidsensing ion channel 1 (ASICI), Calcitonin gene related peptide (CGRP),Tyrosine hydroxylase, Substance P, Neuropeptide Y (NPY), 5HT3-receptor,P2X3, CaV channel. K+ channel, NaV channel, Transient Receptor PotentialVanilloid (TRPV) channel, Transient receptor potential cation channelsubfamily M member 8 (TRPM8), Transient receptor potential cationchannel subfamily A member 1 (TRPAI), Transient receptor potentialcation channel subfamily C member 6 (TRPC6), Vesicular GlutamateTransporter 1 and 2 (VGLUTI/2) and Parvalbumin. Without wishing to bebound by any theory or mechanism, introducing at least onephotosensitizer bound to a neural-specific antibody into at least onelayer of the duodenal wall enables selectively causing damage to neuronswithin target areas illuminated with light suitable for PDT or PIT.

According to some embodiments, the disclosed method further comprisesintroducing into at least one layer of the duodenal wall and/or an areain contact with the duodenal wall at least one photosensitizerconfigured to induce damage to a target area when illuminated with aPDT-compatible light source.

According to some embodiments, the present disclosure provides a methodfor blocking at least part of the neural activity in a duodenum of asubject in need thereof, the method comprising:

-   -   introducing at least one photosensitizer to a target area within        or in contact with at least part of a duodenal wall, wherein the        target area comprises neurons, typically sensory neurons, and        wherein said photosensitizer is configured to selectively cause        damage to said target area when receiving radiation, typically        laser radiation; introducing at least one radiation emitting        element, typically a laser element, into a lumen of the        subject's duodenum;    -   actuating the radiation emitting element to emit radiation, such        as, but not limited to, laser radiation, wherein said radiation        is configured to induce said photosensitizer to cause damage;    -   focusing the radiation to said target area, thereby causing        damage within the target area while maintaining functional        activity of tissue surrounding the target area. Each possibility        represents a separate embodiment of the present invention.

According to some embodiments, the present disclosure provides a methodfor blocking at least part of the neural activity in a duodenum of asubject in need thereof, the method comprising:

-   -   introducing to a target area within or in contact with at least        part of a duodenal wall at least one photosensitizer configured        to selectively bind and/or enter neurons, wherein the target        area comprises sensory nerves, and wherein said photosensitizer        is configured to selectively cause damage to said target area        when receiving laser radiation;    -   introducing at least one laser element into a lumen of the        subject's duodenum;    -   actuating the laser element to emit laser radiation, wherein        said laser radiation is configured to induce said        photosensitizer to cause damage;    -   focusing the laser radiation to said target area, thereby        causing damage to neurons within the target area while        maintaining functional activity of tissue surrounding said        neurons.

XI. Pigments and Photosensitizer

According to some embodiments, the disclosed methods compriseintroducing at least one pigment to at least one layer of at least partof an organ, such as the duodenum and/or the duodenal wall and/or to anarea in contact with the duodenal wall. Each possibility represents aseparate embodiment of the present disclosure. According to someembodiments, the pigment is configured to have higher light and/orenergy absorbance than the tissue to which it is introduced. Eachpossibility represents a separate embodiment of the present disclosure.According to some embodiments, the at least one pigment is introducedtogether with at least one photosensitizer. Without wishing to be boundby any theory or mechanism, introduction of a pigment into a tissue suchthat the pigment has higher absorbance than the tissue enhances theratio between the impact of the laser radiation applied to the tissueand the lateral energy absorption of the tissue. According to someembodiments, the pigment enhances the energy absorbance of the targetarea to which it is introduced. According to some embodiments, thepigment is coupled with and/or connected to an antibody, an antibodyfragment or an antigen binding fragment. Each possibility represents aseparate embodiment of the present disclosure. According to someembodiments, the pigment is nanoparticle or liposome encapsulated. Eachpossibility represents a separate embodiment of the present disclosure.

According to some embodiments, the disclosed method further comprisesintroducing into at least one layer of the duodenal wall and/or an areain contact with the duodenal wall at least one pigment. According tosome embodiments, the disclosed method further comprises introducinginto at least one layer of the duodenal wall and/or an area in contactwith the duodenal wall at least one pigment having higher absorbancethan that of the tissue to which it is introduced.

A non-limiting example of a pigment which may be used according to thepresent disclosure is a Squaraine dye with a peak of absorption at about630 nm. According to some embodiments, the pigment is configured toenable safe use and absorption in the near infra-red spectrum. Accordingto some embodiments, the pigment may be designed to enable safe use andabsorption in the near infra-red spectrum using methods such as, but notlimited to, the Pariser-Pam-Pople molecular orbital method for theidentification of near-infrared absorbing pigment candidates. Accordingto some embodiments, Squaraine dye with a peak of absorption at about630 nm may be used as a photosensitizer.

According to some embodiments, the blocking of the signals triggered byfood, either by chemical sensors or mechanical sensors, may alsomodulate motility related functions of the GI tract organs, such asmodulation of gastric accommodation and relaxation triggered by mealpassing through the duodenum and/or stomach based on the principles inthe prior art or direct impact on motility of a specific site. Eachpossibility represents a separate embodiment of the present disclosure.

Embodiments herein presented and similar can be used in otherendoluminal applications that require impact of nerves surrounding thelumen, such as impact, damage, injury of nerves surrounding vessels asin renal denervation. The motivation for using these embodiments insteadof the conventional RF based catheters is to enable more effectiveimpact on nerves with minimization of lateral damage.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingcurrent knowledge, readily modify and/or adapt for various applicationssuch specific embodiments without undue experimentation and withoutdeparting from the generic concept, and, therefore, such adaptations andmodifications should and are intended to be comprehended within themeaning and range of equivalents of the disclosed embodiments. It is tobe understood that the phraseology or terminology employed herein is forthe purpose of description and not of limitation. The means, materials,and steps for carrying out various disclosed functions may take avariety of alternative forms without departing from the invention.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced be interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

The invention claimed is:
 1. A catheter for reducing neural activity ina submucosal layer of a duodenum of a subject, the catheter comprising:an elongate catheter body having a proximal end and a distal end; alaser emitting element coupled with the catheter body and configured toemit a laser beam having a beam diameter in a range of 1-20 mm in afirst direction parallel to a longitudinal axis of said catheter body; arotatable optical element comprising a focusing lens coupled with thelaser emitting element and configured to direct and focus the beam to beessentially perpendicular to the longitudinal axis of the laser emittingdevice, wherein the focusing lens has a focal length in a range of 2-25mm and a focal plane in a depth in a range of tens of microns, andwherein the focusing lens is optically arranged so as to focus the laserbeam below a mucosal layer of the duodenum so as to ensure that thefocused laser beam exceeds an ablation threshold at the focal plane,while being below the ablation threshold in the duodenum's muscularislayer; and at least one pressure-inducing element coupled with thecatheter body and configured to exert pressure on at least part of theduodenum to obtain a fixed diameter thereof and to position thesubmucosal layer within the focal plane of the focused laser radiation;wherein the catheter is configured to ablate an area of the submucosallayer including sensory neurons, while maintaining functional activityof the mucosal layer and muscle tissue around the area.
 2. The catheterof claim 1, wherein the laser emitting element comprises at least oneoptical fiber.
 3. The catheter of claim 1, wherein the rotatable opticalelement comprises a rotatable prism.
 4. The catheter of claim 1, whereinthe laser beam is in a range of 808 nm, 980 nm or 1500 nm.
 5. Thecatheter of claim 1, further comprising an actuator coupled with therotatable optical element for rotating the rotatable optical element anda controller coupled with the actuator for controlling the actuator inaccordance with an input signal from an input device.
 6. The catheter ofclaim 1, wherein the rotatable optical element comprises a partiallyreflective mirror configured to enable laser radiation to be reflectedback from the submucosal layer.
 7. The catheter of claim 6, furthercomprising collecting the back-reflected laser radiation, utilizing animaging element.
 8. The catheter of claim 1, wherein the catheter bodyhas an outer diameter selected to fit through a lumen of an endoscope.9. The catheter of claim 1, wherein the laser emitting element isconfigured to emit the laser beam along a circular and/or cylindricaltrajectory.
 10. The catheter of claim 1, wherein the at least onepressure-inducing element comprises a balloon.
 11. The catheter of claim1, further comprising collecting at least a portion of a scatteredradiation resulting from ef the emission of the laser beam, utilizing animaging element.
 12. The catheter of claim 1, wherein said laserradiation is configured to heat the area to a temperature above 45° C.13. A system for reducing neural activity in a submucosal layer of aduodenum of a subject, the system comprising: a catheter comprising: anelongate catheter body having a proximal end and a distal end; a laseremitting element coupled with the catheter body at the distal end andconfigured to emit a laser beam having a beam diameter in a range of1-20 mm, in a first direction parallel to a longitudinal axis of saidcatheter body; a rotatable optical element comprising a focusing lenscoupled with the laser emitting element and configured to direct andfocus the beam to be essentially perpendicular to the longitudinal axisof the laser emitting device, wherein the focusing lens has a focallength in a range of 2-25 mm and a focal plane in a depth in a range oftens of microns, and wherein the focusing lens is optically arranged soas to focus the laser beam below a mucosal layer of the duodenum so asto ensure that the focused laser beam exceeds an ablation threshold atthe focal plane, while being below the ablation threshold in theduodenum's muscularis layer; and at least one pressure-inducing elementcoupled with the catheter body and configured to exert pressure on atleast part of the duodenum to obtain a fixed diameter thereof and toposition the submucosal layer within the focal plane of the focusedlaser radiation; wherein the catheter is configured to ablate an area ofthe submucosal layer including sensory neurons, while maintainingfunctional activity of the mucosal layer and muscle tissue around thearea; and an imaging device configured to capture structural informationrelated to the duodenum, based on a beam deflected by said opticalelement and directed to a light detector.
 14. The system of claim 13,wherein said imaging device is configured to capture the structuralinformation on-line by monitoring changes in optical characteristics ofthe duodenum in response to the laser beam.
 15. The system of claim 13,further comprising a controller configured to determine the pressureexerted by the at least one pressure-inducing element.
 16. The system ofclaim 13, wherein the at least one pressure-inducing element comprises aballoon.